diff --git a/pkgs/development/python-modules/tpm2-pytss/cross.patch b/pkgs/development/python-modules/tpm2-pytss/cross.patch
new file mode 100644
index 000000000000..8fa2956c11d0
--- /dev/null
+++ b/pkgs/development/python-modules/tpm2-pytss/cross.patch
@@ -0,0 +1,22 @@
+diff --git a/setup.py b/setup.py
+index 1b5f513..d660b9a 100644
+--- a/setup.py
++++ b/setup.py
+@@ -184,7 +184,8 @@ class type_generator(build_ext):
+                 f"unable to find tss2_tpm2_types.h in {pk['include_dirs']}"
+             )
+         pdata = preprocess_file(
+-            header_path, cpp_args=["-D__extension__=", "-D__attribute__(x)="]
++            header_path, cpp_args=["-D__extension__=", "-D__attribute__(x)="],
++            cpp_path="@crossPrefix@-cpp",
+         )
+         parser = c_parser.CParser()
+         ast = parser.parse(pdata, "tss2_tpm2_types.h")
+@@ -210,6 +211,7 @@ class type_generator(build_ext):
+                         "-D__float128=long double",
+                         "-D_FORTIFY_SOURCE=0",
+                     ],
++                    cpp_path="@crossPrefix@-cpp",
+                 )
+                 parser = c_parser.CParser()
+                 past = parser.parse(pdata, "tss2_policy.h")
diff --git a/pkgs/development/python-modules/tpm2-pytss/default.nix b/pkgs/development/python-modules/tpm2-pytss/default.nix
index 484f3dc2d16e..7b5fd56b0a10 100644
--- a/pkgs/development/python-modules/tpm2-pytss/default.nix
+++ b/pkgs/development/python-modules/tpm2-pytss/default.nix
@@ -1,4 +1,6 @@
 { lib
+, stdenv
+, substituteAll
 , buildPythonPackage
 , fetchPypi
 , pythonOlder
@@ -17,6 +19,9 @@
 , swtpm
 }:
 
+let
+  isCross = (stdenv.buildPlatform != stdenv.hostPlatform);
+in
 buildPythonPackage rec {
   pname = "tpm2-pytss";
   version = "2.2.1";
@@ -32,6 +37,18 @@ buildPythonPackage rec {
   patches = [
     # Fix hardcoded `fapi-config.json` configuration path
     ./fapi-config.patch
+  ] ++ lib.optionals isCross [
+    # pytss will regenerate files from headers of tpm2-tss.
+    # Those headers are fed through a compiler via pycparser. pycparser expects `cpp`
+    # to be in the path.
+    # This is put in the path via stdenv when not cross-compiling, but this is absent
+    # when cross-compiling is turned on.
+    # This patch changes the call to pycparser.preprocess_file to provide the name
+    # of the cross-compiling cpp
+    (substituteAll {
+      src = ./cross.patch;
+      crossPrefix = stdenv.hostPlatform.config;
+    })
   ];
 
   postPatch = ''