diff --git a/CHANGELOG.md b/CHANGELOG.md
index d2487213..ef90d7bf 100644
--- a/CHANGELOG.md
+++ b/CHANGELOG.md
@@ -5,6 +5,15 @@ All notable changes to this project will be documented in this file.
 The format is based on [Keep a Changelog](https://keepachangelog.com/en/1.0.0/),
 and this project adheres to [Semantic Versioning](https://semver.org/spec/v2.0.0.html).
 
+## Unreleased
+
+### Fixed
+
+- Fixed an include path issue on macOS when homebrew Python is installed:
+  if `sys.prefix` contains a symlink (as is the case with homebrew), resolve it
+  so that host include paths are still replaced by the cross-compile ones
+  [#375](https://github.com/pyodide/pyodide-build/pull/375)
+
 ## [0.35.0] - 2026/06/09
 
 ### Added
diff --git a/pyodide_build/pywasmcross.py b/pyodide_build/pywasmcross.py
index 80a6c24f..375937c2 100755
--- a/pyodide_build/pywasmcross.py
+++ b/pyodide_build/pywasmcross.py
@@ -161,14 +161,14 @@ def replay_genargs_handle_dashI(arg: str, target_install_dir: str) -> str | None
     if include_path_str.startswith("/usr"):
         return None
 
-    # Replace local Python include paths with the cross compiled ones
+    # Replace local Python include paths with the cross compiled ones.
+    # (resolve symlinks, since on macOS/homebrew Python sys.prefix will contain a symlink)
     include_path = str(Path(include_path_str).resolve())
 
-    if include_path.startswith(sys.prefix + "/include/python"):
-        return arg.replace("-I" + sys.prefix, "-I" + target_install_dir)
-
-    if include_path.startswith(sys.base_prefix + "/include/python"):
-        return arg.replace("-I" + sys.base_prefix, "-I" + target_install_dir)
+    for prefix in (sys.prefix, sys.base_prefix):
+        prefix = str(Path(prefix).resolve())
+        if include_path.startswith(prefix + "/include/python"):
+            return "-I" + target_install_dir + include_path.removeprefix(prefix)
 
     return arg
 
diff --git a/pyodide_build/tests/test_pywasmcross.py b/pyodide_build/tests/test_pywasmcross.py
index 9292b15c..8f6f5928 100644
--- a/pyodide_build/tests/test_pywasmcross.py
+++ b/pyodide_build/tests/test_pywasmcross.py
@@ -147,6 +147,27 @@ def test_replay_genargs_handle_dashI(monkeypatch):
     )
 
 
+def test_replay_genargs_handle_dashI_symlinked_prefix(monkeypatch, tmp_path):
+    # sys.prefix may contain a symlink (e.g. homebrew Python on macOS:
+    # /opt/homebrew/opt/python@X.Y -> ../Cellar/...); the include path must be
+    # recognized nonetheless.
+    import sys
+
+    real_prefix = tmp_path / "Cellar" / "python3.11"
+    (real_prefix / "include" / "python3.11").mkdir(parents=True)
+    link_prefix = tmp_path / "opt" / "python3.11"
+    link_prefix.parent.mkdir()
+    link_prefix.symlink_to(real_prefix)
+
+    monkeypatch.setattr(sys, "prefix", str(link_prefix))
+    monkeypatch.setattr(sys, "base_prefix", str(link_prefix))
+
+    assert (
+        replay_genargs_handle_dashI(f"-I{link_prefix}/include/python3.11", "/target")
+        == "-I/target/include/python3.11"
+    )
+
+
 def test_conda_unsupported_args(build_args):
     # Check that compile arguments that are not supported by emcc and are sometimes
     # used in conda are removed.