diff --git a/pkgs/development/libraries/protobuf/generic.nix b/pkgs/development/libraries/protobuf/generic.nix
index 91e6bc878b01..29e4988bf52d 100644
--- a/pkgs/development/libraries/protobuf/generic.nix
+++ b/pkgs/development/libraries/protobuf/generic.nix
@@ -89,6 +89,14 @@ stdenv.mkDerivation (finalAttrs: {
       substituteInPlace src/google/protobuf/testing/googletest.cc \
         --replace-fail 'tmpnam(b)' '"'$TMPDIR'/foo"'
     ''
+    # Adapt https://github.com/protocolbuffers/protobuf/pull/22412 for various
+    # older versions. sed -z spans newlines, so this can capture and replace
+    # the full multiline #if macro.
+    + lib.optionalString (lib.versionOlder version "32") ''
+      sed -zi 's/\(#if \w*(clang::musttail)\)[^\n]*\(\\\n[^\n]*\)*/'\
+      '\1 \&\& (defined(__aarch64__) || defined(__x86_64__) || defined(_M_X64))/' \
+        src/google/protobuf/port_def.inc
+    ''
     # Keep the sentinel macro non-retained for GCC 15+ to match generated
     # extension objects in linker arrays and avoid section type conflicts.
     + lib.optionalString (lib.versionAtLeast version "34") ''