diff --git a/.github/workflows/icu_ci.yml b/.github/workflows/icu_ci.yml
index d0936c4..e178fcf 100644
--- a/.github/workflows/icu_ci.yml
+++ b/.github/workflows/icu_ci.yml
@@ -252,3 +252,17 @@
     steps:
       - uses: actions/checkout@v2
       - run: mvn -f tools/release/java/pom.xml package dependency:analyze
+
+  # Run unit tests with UCONFIG_NO_XXX variations.
+  uconfig_variation-check-unit-tests:
+    runs-on: ubuntu-latest
+    steps:
+      - uses: actions/checkout@v2
+      - run: python3 tools/scripts/uconfig_vars_test.py -u
+
+# Run header tests with UCONFIG_NO_XXX variations.
+  uconfig_variation-check-all-header-tests:
+    runs-on: ubuntu-latest
+    steps:
+      - uses: actions/checkout@v2
+      - run: python3 tools/scripts/uconfig_vars_test.py -p
diff --git a/icu4c/source/test/hdrtst/Makefile.in b/icu4c/source/test/hdrtst/Makefile.in
index af0e848..5e640a4 100644
--- a/icu4c/source/test/hdrtst/Makefile.in
+++ b/icu4c/source/test/hdrtst/Makefile.in
@@ -17,6 +17,10 @@
 ##
 ##    .. etc.  Anything other than zero is an error. (except for the deprecation tests, where '1' is the correct value)
 ##
+##  If the header test is run for a particular UCONFIG_NO_XXX=1 variation (see uconfig.h)
+##  then invoke the test with 'make UCONFIG_NO="-DUCONFIG_NO_XXX=1 check'.
+##  For standard header test run the UCONFIG_NO variable will evaluate to empty string.
+##
 ##  If a header fails the C compile test it is likely because the header is a
 ##  C++ header and it isn't properly guarded by the U_SHOW_CPLUSPLUS_API macro.
 ##
@@ -48,7 +52,7 @@
 		echo "$(NAME.headers) unicode/$$incfile" ; \
 		echo "#include <unicode/$$incfile>" > $$stub ; \
 		echo 'void junk(){}' >> $$stub ; \
-		$(COMPILE.headers) $(cppflags) $(FLAGS.headers) $$stub || FAIL=1 ; \
+		$(COMPILE.headers) $(cppflags) $(FLAGS.headers) $(UCONFIG_NO) $$stub || FAIL=1 ; \
 		rm -f $$stub; \
 	done ; \
 	exit $$FAIL
@@ -121,7 +125,7 @@
 			echo '#if !defined(U_SHOW_CPLUSPLUS_API)' >> $$stub ; \
 			echo "#error The header '$$incfile' refers to the macro U_SHOW_CPLUSPLUS_API (defined in utypes.h) but either does not include utypes.h or does so incorrectly." >> $$stub ; \
 			echo '#endif' >> $$stub ; \
-			$(COMPILE.cc) $(cppflags) $$stub || FAIL=1 ; \
+			$(COMPILE.cc) $(cppflags) $(UCONFIG_NO) $$stub || FAIL=1 ; \
 			rm -f $$stub; \
 		else \
 			echo "$@ skipping unicode/$$incfile" ; \
diff --git a/tools/scripts/uconfig_vars_test.py b/tools/scripts/uconfig_vars_test.py
new file mode 100755
index 0000000..226ff1d
--- /dev/null
+++ b/tools/scripts/uconfig_vars_test.py
@@ -0,0 +1,219 @@
+# © 2021 and later: Unicode, Inc. and others.
+# License & terms of use: http://www.unicode.org/copyright.html
+
+"""Executes uconfig variations check.
+
+See
+http://site.icu-project.org/processes/release/tasks/healthy-code#TOC-Test-uconfig.h-variations
+for more information.
+"""
+
+import getopt
+import os
+import re
+import subprocess
+import sys
+
+excluded_unit_test_flags = ['UCONFIG_NO_CONVERSION', 'UCONFIG_NO_FILE_IO'];
+
+def ReadFile(filename):
+    """Reads a file and returns the content of the file
+
+    Args:
+      command: string with the filename.
+
+    Returns:
+      Content of file.
+    """
+
+    with open(filename, 'r') as file_handle:
+      return file_handle.read()
+
+def RunCmd(command):
+    """Executes the command, returns output and exit code, writes output to log
+
+    Args:
+      command: string with the command.
+
+    Returns:
+      stdout and exit code of command execution.
+    """
+
+    command += ' >> uconfig_test.log 2>&1'
+    print(command)
+    p = subprocess.Popen(command, shell=True, stdout=subprocess.PIPE,
+                         stderr=subprocess.STDOUT, close_fds=True)
+    stdout, _ = p.communicate()
+    return stdout, p.returncode
+
+def ExtractUConfigNoXXX(uconfig_file):
+    """Parses uconfig.h and returns a list of UCONFIG_NO_XXX labels.
+    Initializes test result structure.
+
+    Args:
+      uconfig_file: common/unicode/uconfig.h as string.
+
+    Returns:
+      List of all UCONFIG_NO_XXX flags found in uconfig.h, initialized test
+      result structure.
+    """
+
+    uconfig_no_flags_all = []
+    test_results = {}
+    uconfig_no_regex = r'UCONFIG_NO_[A-Z_]*'
+
+    # Collect all distinct occurences of UCONFIG_NO_XXX matches in uconfig.h.
+    for uconfig_no_flag in re.finditer(uconfig_no_regex, uconfig_file):
+        if uconfig_no_flag.group(0) not in uconfig_no_flags_all:
+            uconfig_no_flags_all.append(uconfig_no_flag.group(0))
+
+    # All UCONFIG_NO_XXX flags found in uconfig.h come in form of a guarded
+    # definition. Verify the existence, report error if not found.
+    for uconfig_no_flag in uconfig_no_flags_all:
+        uconfig_no_def_regex = r'(?m)#ifndef %s\n#\s+define %s\s+0\n#endif$' % (
+        uconfig_no_flag, uconfig_no_flag)
+        uconfig_no_def_match = re.search(uconfig_no_def_regex, uconfig_file)
+        if not uconfig_no_def_match:
+            print('No definition for flag %s found!\n' % uconfig_no_flag)
+            sys.exit(1)
+
+    test_results = {f: {'unit_test': False, 'hdr_test': False} for f in uconfig_no_flags_all}
+    test_results['all_flags'] = {'unit_test': False, 'hdr_test' : False}
+
+    return uconfig_no_flags_all, test_results
+
+def BuildAllFlags(uconfig_no_list):
+    """Builds sequence of -Dflag=1 with each flag from the list."""
+
+    flag_list = ['-D' + uconfig_no + '=1' for uconfig_no in uconfig_no_list]
+
+    return ' '.join(flag_list)
+
+def RunUnitTests(uconfig_no_list, test_results):
+    """Iterates over all flags, sets each individually during ICU configuration
+       and executes the ICU4C unit tests.
+
+    Args:
+      uconfig_no_list: list of all UCONFIG_NO_XXX flags to test with.
+      test_results: dictionary to record test run results.
+
+    Returns:
+      test_results: updated test result entries.
+    """
+
+    for uconfig_no in uconfig_no_list:
+        _, exit_code = RunCmd(
+                './runConfigureICU Linux CPPFLAGS=\"-D%s=1"' % uconfig_no)
+        if exit_code != 0:
+            print('ICU4C configuration for flag %s failed' % uconfig_no)
+            sys.exit(1)
+        print('Running unit tests with %s set to 1.' % uconfig_no)
+        _, exit_code = RunCmd('make -j2 check')
+        test_results[uconfig_no]['unit_test'] = (exit_code == 0)
+        RunCmd('make clean')
+
+    # Configure ICU with all UCONFIG_NO_XXX flags set to 1 and execute
+    # the ICU4C unit tests.
+    all_unit_test_config_no = BuildAllFlags(uconfig_no_list)
+    _, exit_code = RunCmd(
+        'CPPFLAGS=\"%s\" ./runConfigureICU Linux' % all_unit_test_config_no)
+    if exit_code != 0:
+        print('ICU configuration with all flags set failed')
+        sys.exit(1)
+    print('Running unit tests with all flags set to 1.')
+    _, exit_code = RunCmd('make -j2 check')
+    test_results['all_flags']['unit_test'] = (exit_code == 0)
+    RunCmd('make clean')
+
+    return test_results
+
+def RunHeaderTests(uconfig_no_list, test_results):
+    """Iterates over all flags and executes the header test.
+
+    Args:
+      uconfig_no_list: list of all UCONFIG_NO_XXX flags to test with.
+      test_results: dictionary to record test run results.
+
+    Returns:
+      test_results: updated test result entries.
+    """
+
+    # Header tests needs different setup.
+    RunCmd('mkdir /tmp/icu_cnfg')
+    out, exit_code = RunCmd('./runConfigureICU Linux --prefix=/tmp/icu_cnfg')
+    if exit_code != 0:
+        print('ICU4C configuration for header test failed!')
+        print(out)
+        sys.exit(1)
+
+    _, exit_code = RunCmd('make -j2 install')
+    if exit_code != 0:
+        print('make install failed!')
+        sys.exit(1)
+
+    for uconfig_no in uconfig_no_list:
+        print('Running header tests with %s set to 1.' % uconfig_no)
+        _, exit_code = RunCmd(
+            'PATH=/tmp/icu_cnfg/bin:$PATH make -C test/hdrtst UCONFIG_NO=\"-D%s=1\" check' % uconfig_no)
+        test_results[uconfig_no]['hdr_test'] = (exit_code == 0)
+
+    all_hdr_test_flags = BuildAllFlags(uconfig_no_list)
+    print('Running header tests with all flags set to 1.')
+    _, exit_code = RunCmd(
+        'PATH=/tmp/icu_cnfg/bin:$PATH make -C test/hdrtst UCONFIG_NO=\"%s\" check' % all_hdr_test_flags)
+    test_results['all_flags']['hdr_test'] = (exit_code == 0)
+
+    return test_results
+
+def main():
+    # Read the options and determine what to run.
+    run_hdr = False
+    run_unit = False
+    optlist, _ = getopt.getopt(sys.argv[1:], "pu")
+    for o, _ in optlist:
+        if o == "-p":
+            run_hdr = True
+        elif o == "-u":
+            run_unit = True
+
+    os.chdir('icu4c/source')
+    orig_uconfig_file = ReadFile('common/unicode/uconfig.h')
+
+    all_uconfig_no_flags, test_results = ExtractUConfigNoXXX(orig_uconfig_file)
+    if not all_uconfig_no_flags:
+        print('No UCONFIG_NO_XXX flags found!\n')
+        sys.exit(1)
+
+    if run_unit:
+        RunUnitTests(
+            [u for u in all_uconfig_no_flags if u not in excluded_unit_test_flags],
+            test_results)
+    if run_hdr:
+        RunHeaderTests(all_uconfig_no_flags, test_results)
+
+    # Review test results and report any failures.
+    # 'outcome' will be returned by sys.exit(); 0 indicates success, any
+    # other value indicates failure.
+    outcome = 0
+    print('Summary:\n')
+    for uconfig_no in all_uconfig_no_flags:
+        if run_unit and (uconfig_no not in excluded_unit_test_flags):
+            if not test_results[uconfig_no]['unit_test']:
+                outcome = 1
+                print('%s: unit tests fail' % uconfig_no)
+        if run_hdr and not test_results[uconfig_no]['hdr_test']:
+            outcome = 1
+            print('%s: header tests fails' % uconfig_no)
+    if run_unit and not test_results['all_flags']['unit_test']:
+        outcome = 1
+        print('all flags to 1: unit tests fail!')
+    if run_hdr and not test_results['all_flags']['hdr_test']:
+        outcome = 1
+        print('all flags to 1: header tests fail!')
+    if outcome == 0:
+        print('Tests pass for all uconfig variations!')
+    sys.exit(outcome)
+
+
+if __name__ == '__main__':
+  main()