diff --git a/Misc/NEWS.d/next/Build/2021-11-05-20-56-29.bpo-45731.9SDnDf.rst b/Misc/NEWS.d/next/Build/2021-11-05-20-56-29.bpo-45731.9SDnDf.rst
new file mode 100644
index 00000000000..1e490fac6ee
--- /dev/null
+++ b/Misc/NEWS.d/next/Build/2021-11-05-20-56-29.bpo-45731.9SDnDf.rst
@@ -0,0 +1 @@
+``configure --enable-loadable-sqlite-extensions`` is now handled by new ``PY_SQLITE_ENABLE_LOAD_EXTENSION`` macro instead of logic in setup.py.
diff --git a/Modules/_sqlite/clinic/connection.c.h b/Modules/_sqlite/clinic/connection.c.h
index f9323eb21d6..4e5ee500ad1 100644
--- a/Modules/_sqlite/clinic/connection.c.h
+++ b/Modules/_sqlite/clinic/connection.c.h
@@ -367,7 +367,7 @@ exit:
     return return_value;
 }
 
-#if !defined(SQLITE_OMIT_LOAD_EXTENSION)
+#if defined(PY_SQLITE_ENABLE_LOAD_EXTENSION)
 
 PyDoc_STRVAR(pysqlite_connection_enable_load_extension__doc__,
 "enable_load_extension($self, enable, /)\n"
@@ -398,9 +398,9 @@ exit:
     return return_value;
 }
 
-#endif /* !defined(SQLITE_OMIT_LOAD_EXTENSION) */
+#endif /* defined(PY_SQLITE_ENABLE_LOAD_EXTENSION) */
 
-#if !defined(SQLITE_OMIT_LOAD_EXTENSION)
+#if defined(PY_SQLITE_ENABLE_LOAD_EXTENSION)
 
 PyDoc_STRVAR(pysqlite_connection_load_extension__doc__,
 "load_extension($self, name, /)\n"
@@ -440,7 +440,7 @@ exit:
     return return_value;
 }
 
-#endif /* !defined(SQLITE_OMIT_LOAD_EXTENSION) */
+#endif /* defined(PY_SQLITE_ENABLE_LOAD_EXTENSION) */
 
 PyDoc_STRVAR(pysqlite_connection_execute__doc__,
 "execute($self, sql, parameters=<unrepresentable>, /)\n"
@@ -834,4 +834,4 @@ exit:
 #ifndef PYSQLITE_CONNECTION_LOAD_EXTENSION_METHODDEF
     #define PYSQLITE_CONNECTION_LOAD_EXTENSION_METHODDEF
 #endif /* !defined(PYSQLITE_CONNECTION_LOAD_EXTENSION_METHODDEF) */
-/*[clinic end generated code: output=0c3901153a3837a5 input=a9049054013a1b77]*/
+/*[clinic end generated code: output=d71bf16bef67878f input=a9049054013a1b77]*/
diff --git a/Modules/_sqlite/connection.c b/Modules/_sqlite/connection.c
index f913267e156..964673a6125 100644
--- a/Modules/_sqlite/connection.c
+++ b/Modules/_sqlite/connection.c
@@ -1225,7 +1225,7 @@ pysqlite_connection_set_trace_callback_impl(pysqlite_Connection *self,
     Py_RETURN_NONE;
 }
 
-#ifndef SQLITE_OMIT_LOAD_EXTENSION
+#ifdef PY_SQLITE_ENABLE_LOAD_EXTENSION
 /*[clinic input]
 _sqlite3.Connection.enable_load_extension as pysqlite_connection_enable_load_extension
 
diff --git a/configure b/configure
index 00bea712b06..1eea2d13205 100755
--- a/configure
+++ b/configure
@@ -10913,13 +10913,20 @@ $as_echo_n "checking for --enable-loadable-sqlite-extensions... " >&6; }
 if test "${enable_loadable_sqlite_extensions+set}" = set; then :
   enableval=$enable_loadable_sqlite_extensions;
 else
-  enable_loadable_sqlite_extensions="no"
+  enable_loadable_sqlite_extensions=no
 fi
 
-
 { $as_echo "$as_me:${as_lineno-$LINENO}: result: $enable_loadable_sqlite_extensions" >&5
 $as_echo "$enable_loadable_sqlite_extensions" >&6; }
 
+if test "x$enable_loadable_sqlite_extensions" = xyes; then :
+
+
+$as_echo "#define PY_SQLITE_ENABLE_LOAD_EXTENSION 1" >>confdefs.h
+
+
+fi
+
 # Check for --with-tcltk-includes=path and --with-tcltk-libs=path
 
 
diff --git a/configure.ac b/configure.ac
index ea119085ab1..8895818d19d 100644
--- a/configure.ac
+++ b/configure.ac
@@ -3199,10 +3199,14 @@ AC_ARG_ENABLE(loadable-sqlite-extensions,
               AS_HELP_STRING([--enable-loadable-sqlite-extensions],
                              [support loadable extensions in _sqlite module, see Doc/library/sqlite3.rst (default is no)]),
               [],
-              [enable_loadable_sqlite_extensions="no"])
-
+              [enable_loadable_sqlite_extensions=no])
 AC_MSG_RESULT($enable_loadable_sqlite_extensions)
 
+AS_VAR_IF([enable_loadable_sqlite_extensions], [yes], [
+  AC_DEFINE(PY_SQLITE_ENABLE_LOAD_EXTENSION, 1,
+  [Define to 1 to build the sqlite module with loadable extensions support.])
+])
+
 # Check for --with-tcltk-includes=path and --with-tcltk-libs=path
 AC_SUBST(TCLTK_INCLUDES)
 AC_SUBST(TCLTK_LIBS)
diff --git a/pyconfig.h.in b/pyconfig.h.in
index b89377dc1b4..0c149e24bca 100644
--- a/pyconfig.h.in
+++ b/pyconfig.h.in
@@ -1395,6 +1395,9 @@
 /* Define to printf format modifier for Py_ssize_t */
 #undef PY_FORMAT_SIZE_T
 
+/* Define to 1 to build the sqlite module with loadable extensions support. */
+#undef PY_SQLITE_ENABLE_LOAD_EXTENSION
+
 /* Default cipher suites list for ssl module. 1: Python's preferred selection,
    2: leave OpenSSL defaults untouched, 0: custom string */
 #undef PY_SSL_DEFAULT_CIPHERS
diff --git a/setup.py b/setup.py
index 22c5ccf0a07..b6bf8e12937 100644
--- a/setup.py
+++ b/setup.py
@@ -1602,9 +1602,11 @@ def detect_sqlite(self):
 
             # Enable support for loadable extensions in the sqlite3 module
             # if --enable-loadable-sqlite-extensions configure option is used.
-            if '--enable-loadable-sqlite-extensions' not in sysconfig.get_config_var("CONFIG_ARGS"):
-                sqlite_defines.append(("SQLITE_OMIT_LOAD_EXTENSION", "1"))
-            elif MACOS and sqlite_incdir == os.path.join(MACOS_SDK_ROOT, "usr/include"):
+            if (
+                MACOS and
+                sqlite_incdir == os.path.join(MACOS_SDK_ROOT, "usr/include") and
+                sysconfig.get_config_var("PY_SQLITE_ENABLE_LOAD_EXTENSION")
+            ):
                 raise DistutilsError("System version of SQLite does not support loadable extensions")
 
             if MACOS: