diff --git a/cibuildwheel/platforms/pyodide.py b/cibuildwheel/platforms/pyodide.py
index 444c55a4..2466d59d 100644
--- a/cibuildwheel/platforms/pyodide.py
+++ b/cibuildwheel/platforms/pyodide.py
@@ -218,6 +218,36 @@ def validate_pyodide_build_version(
         raise errors.FatalError(msg)
 
 
+def validate_pyodide_target_python(
+    xbuildenv_info: PyodideXBuildEnvInfo, python_configuration: PythonConfiguration
+) -> None:
+    """
+    Validate that the resolved Pyodide xbuildenv targets the same Python version
+    as the identifier being built.
+
+    This is to catch the case where a global ``pyodide-version`` is applied to an
+    identifier whose Python version does not match, such as setting
+    ``pyodide-version = "3Y.0.0"`` (a Python 3.Y environment) while
+    building ``cp3X-pyodide_wasm32``.
+    """
+    xbuildenv_version = xbuildenv_info["version"]
+    identifier = python_configuration.identifier
+    expected_version = python_configuration.version
+    default_version = python_configuration.default_pyodide_version
+    xbuildenv_python_minor = ".".join(xbuildenv_info["python"].split(".")[:2])
+    if xbuildenv_python_minor != expected_version:
+        msg = unwrap_preserving_paragraphs(f"""
+            The `pyodide-version` option is set to {xbuildenv_version}, which
+            provides Python {xbuildenv_python_minor}, but the {identifier} build
+            needs Python {expected_version}.
+
+            Either remove `pyodide-version` so {identifier} uses its default
+            ({default_version}), or stop building {identifier} so that
+            `pyodide-version` only applies to an identifier it matches.
+        """)
+        raise errors.ConfigurationError(msg)
+
+
 def install_xbuildenv(env: dict[str, str], xbuildenv_cache_path: Path, pyodide_version: str) -> str:
     """Install a particular Pyodide xbuildenv version and set a path to the Pyodide root."""
     pyodide_root = xbuildenv_cache_path / pyodide_version / "xbuildenv" / "pyodide-root"
@@ -337,6 +367,10 @@ def setup_python(
         xbuildenv_info=xbuildenv_info,
         pyodide_build_version=pyodide_build_version,
     )
+    validate_pyodide_target_python(
+        xbuildenv_info=xbuildenv_info,
+        python_configuration=python_configuration,
+    )
 
     xbuildenv_cache_path = CIBW_CACHE_PATH / f"pyodide-build-{pyodide_build_version}"
 
diff --git a/unit_test/options_test.py b/unit_test/options_test.py
index aafeb161..f5f8d7a0 100644
--- a/unit_test/options_test.py
+++ b/unit_test/options_test.py
@@ -25,12 +25,19 @@ from cibuildwheel.options import (
     _get_pinned_container_images,
 )
 from cibuildwheel.platforms import ALL_PLATFORM_MODULES, get_build_identifiers
+from cibuildwheel.platforms.pyodide import (
+    PyodideXBuildEnvInfo,
+    validate_pyodide_target_python,
+)
+from cibuildwheel.platforms.pyodide import (
+    PythonConfiguration as PyodidePythonConfiguration,
+)
 from cibuildwheel.util import resources
 from cibuildwheel.util.packaging import DependencyConstraints
 
 TYPE_CHECKING = False
 if TYPE_CHECKING:
-    from collections.abc import Sequence
+    from collections.abc import Callable, Sequence
 
 PYPROJECT_1 = """
 [tool.cibuildwheel]
@@ -106,6 +113,62 @@ def test_options_1(tmp_path: Path, monkeypatch: pytest.MonkeyPatch) -> None:
     assert local.pyodide_version == "0.29.4"
 
 
+@pytest.fixture
+def make_pyodide_xbuildenv_info() -> Callable[[str, str], PyodideXBuildEnvInfo]:
+    def _make(version: str, python: str) -> PyodideXBuildEnvInfo:
+        return {
+            "version": version,
+            "python": python,
+            "emscripten": "5.0.3",
+            "pyodide_build": {"min": None, "max": None},
+            "compatible": True,
+        }
+
+    return _make
+
+
+@pytest.fixture
+def make_pyodide_python_configuration() -> Callable[[str, str], PyodidePythonConfiguration]:
+    def _make(identifier: str, version: str) -> PyodidePythonConfiguration:
+        return PyodidePythonConfiguration(
+            version=version,
+            identifier=identifier,
+            default_pyodide_version="0.0.0",
+            node_version="v22",
+        )
+
+    return _make
+
+
+def test_validate_pyodide_target_python_matching(
+    make_pyodide_xbuildenv_info: Callable[[str, str], PyodideXBuildEnvInfo],
+    make_pyodide_python_configuration: Callable[[str, str], PyodidePythonConfiguration],
+) -> None:
+    xbuildenv_info = make_pyodide_xbuildenv_info("314.0.0", "3.14.2")
+    config = make_pyodide_python_configuration("cp314-pyodide_wasm32", "3.14")
+    # should not raise
+    validate_pyodide_target_python(xbuildenv_info, config)
+
+
+def test_validate_pyodide_target_python_mismatch(
+    make_pyodide_xbuildenv_info: Callable[[str, str], PyodideXBuildEnvInfo],
+    make_pyodide_python_configuration: Callable[[str, str], PyodidePythonConfiguration],
+) -> None:
+    # a Python 3.14 xbuildenv applied to a cp313-pyodide_wasm32 build, when a global
+    # pyodide-version is set across mismatched targets
+    xbuildenv_info = make_pyodide_xbuildenv_info("314.0.0", "3.14.2")
+    config = make_pyodide_python_configuration("cp313-pyodide_wasm32", "3.13")
+
+    with pytest.raises(errors.ConfigurationError) as exc_info:
+        validate_pyodide_target_python(xbuildenv_info, config)
+
+    message = str(exc_info.value)
+    assert "cp313-pyodide_wasm32" in message
+    assert "314.0.0" in message
+    assert "3.13" in message
+    assert "3.14" in message
+
+
 def test_test_and_audit_requires_with_dependency_specifiers(tmp_path: Path) -> None:
     """Regression test for https://github.com/pypa/cibuildwheel/issues/2912"""
     pyproject_toml = tmp_path / "pyproject.toml"