diff --git a/Misc/NEWS.d/next/Build/2021-11-24-17-14-06.bpo-45881.GTXXLk.rst b/Misc/NEWS.d/next/Build/2021-11-24-17-14-06.bpo-45881.GTXXLk.rst
new file mode 100644
index 00000000000..b697658cf3a
--- /dev/null
+++ b/Misc/NEWS.d/next/Build/2021-11-24-17-14-06.bpo-45881.GTXXLk.rst
@@ -0,0 +1,2 @@
+``setup.py`` now uses ``CC`` from environment first to discover multiarch
+and cross compile paths.
diff --git a/setup.py b/setup.py
index 932667ad0c2..79f8f4ef508 100644
--- a/setup.py
+++ b/setup.py
@@ -84,6 +84,9 @@ CYGWIN = (HOST_PLATFORM == 'cygwin')
 MACOS = (HOST_PLATFORM == 'darwin')
 AIX = (HOST_PLATFORM.startswith('aix'))
 VXWORKS = ('vxworks' in HOST_PLATFORM)
+CC = os.environ.get("CC")
+if not CC:
+    CC = sysconfig.get_config_var("CC")
 
 
 SUMMARY = """
@@ -556,6 +559,9 @@ class PyBuildExt(build_ext):
 
     def build_extensions(self):
         self.set_srcdir()
+        self.set_compiler_executables()
+        self.configure_compiler()
+        self.init_inc_lib_dirs()
 
         # Detect which modules should be compiled
         self.detect_modules()
@@ -565,7 +571,6 @@ class PyBuildExt(build_ext):
 
         self.update_sources_depends()
         mods_built, mods_disabled = self.handle_configured_extensions()
-        self.set_compiler_executables()
 
         if LIST_MODULE_NAMES:
             for ext in self.extensions:
@@ -751,12 +756,11 @@ class PyBuildExt(build_ext):
     def add_multiarch_paths(self):
         # Debian/Ubuntu multiarch support.
         # https://wiki.ubuntu.com/MultiarchSpec
-        cc = sysconfig.get_config_var('CC')
         tmpfile = os.path.join(self.build_temp, 'multiarch')
         if not os.path.exists(self.build_temp):
             os.makedirs(self.build_temp)
         ret = run_command(
-            '%s -print-multiarch > %s 2> /dev/null' % (cc, tmpfile))
+            '%s -print-multiarch > %s 2> /dev/null' % (CC, tmpfile))
         multiarch_path_component = ''
         try:
             if ret == 0:
@@ -818,11 +822,10 @@ class PyBuildExt(build_ext):
                 d = os.path.normpath(d)
                 add_dir_to_list(self.compiler.library_dirs, d)
 
-        cc = sysconfig.get_config_var('CC')
         tmpfile = os.path.join(self.build_temp, 'wrccpaths')
         os.makedirs(self.build_temp, exist_ok=True)
         try:
-            ret = run_command('%s --print-search-dirs >%s' % (cc, tmpfile))
+            ret = run_command('%s --print-search-dirs >%s' % (CC, tmpfile))
             if ret:
                 return
             with open(tmpfile) as fp:
@@ -840,11 +843,10 @@ class PyBuildExt(build_ext):
                 pass
 
     def add_cross_compiling_paths(self):
-        cc = sysconfig.get_config_var('CC')
         tmpfile = os.path.join(self.build_temp, 'ccpaths')
         if not os.path.exists(self.build_temp):
             os.makedirs(self.build_temp)
-        ret = run_command('%s -E -v - </dev/null 2>%s 1>/dev/null' % (cc, tmpfile))
+        ret = run_command('%s -E -v - </dev/null 2>%s 1>/dev/null' % (CC, tmpfile))
         is_gcc = False
         is_clang = False
         in_incdirs = False
@@ -1407,9 +1409,6 @@ class PyBuildExt(build_ext):
         # remove dummy extension
         self.extensions = []
 
-        self.configure_compiler()
-        self.init_inc_lib_dirs()
-
         # Some C extensions are built by entries in Modules/Setup.bootstrap.
         # These are extensions are required to bootstrap the interpreter or
         # build process.