diff --git a/mypyc/build.py b/mypyc/build.py
index 8505a2d95701..02f427c83426 100644
--- a/mypyc/build.py
+++ b/mypyc/build.py
@@ -36,7 +36,7 @@
 from mypy.util import write_junit_xml
 from mypyc.annotate import generate_annotated_html
 from mypyc.codegen import emitmodule
-from mypyc.common import IS_FREE_THREADED, RUNTIME_C_FILES, shared_lib_name
+from mypyc.common import IS_FREE_THREADED, RUNTIME_C_FILES, X86_64, shared_lib_name
 from mypyc.errors import Errors
 from mypyc.ir.pprint import format_modules
 from mypyc.namegen import exported_name
@@ -77,6 +77,12 @@ class ModDesc(NamedTuple):
             "base64/arch/generic/enc_tail.c",
             "base64/arch/generic/dec_head.c",
             "base64/arch/generic/dec_tail.c",
+            "base64/arch/ssse3/dec_reshuffle.c",
+            "base64/arch/ssse3/dec_loop.c",
+            "base64/arch/ssse3/enc_loop_asm.c",
+            "base64/arch/ssse3/enc_translate.c",
+            "base64/arch/ssse3/enc_reshuffle.c",
+            "base64/arch/ssse3/enc_loop.c",
             "base64/arch/neon64/dec_loop.c",
             "base64/arch/neon64/enc_loop_asm.c",
             "base64/codecs.h",
@@ -655,6 +661,9 @@ def mypycify(
             # See https://github.com/mypyc/mypyc/issues/956
             "-Wno-cpp",
         ]
+        if X86_64:
+            # Enable SIMD extensions. All CPUs released since ~2010 support SSE4.2.
+            cflags.append("-msse4.2")
         if log_trace:
             cflags.append("-DMYPYC_LOG_TRACE")
         if experimental_features:
@@ -683,6 +692,10 @@ def mypycify(
             # that we actually get the compilation speed and memory
             # use wins that multi-file mode is intended for.
             cflags += ["/GL-", "/wd9025"]  # warning about overriding /GL
+        if X86_64:
+            # Enable SIMD extensions. All CPUs released since ~2010 support SSE4.2.
+            # Also Windows 11 requires SSE4.2 since 24H2.
+            cflags.append("/arch:SSE4.2")
         if log_trace:
             cflags.append("/DMYPYC_LOG_TRACE")
         if experimental_features:
diff --git a/mypyc/common.py b/mypyc/common.py
index 2de63c09bb2c..98f8a89f6fcb 100644
--- a/mypyc/common.py
+++ b/mypyc/common.py
@@ -1,5 +1,6 @@
 from __future__ import annotations
 
+import platform
 import sys
 import sysconfig
 from typing import Any, Final
@@ -44,6 +45,8 @@
 
 IS_32_BIT_PLATFORM: Final = int(SIZEOF_SIZE_T) == 4
 
+X86_64: Final = platform.machine() in ("x86_64", "AMD64", "amd64")
+
 PLATFORM_SIZE = 4 if IS_32_BIT_PLATFORM else 8
 
 # Maximum value for a short tagged integer.
diff --git a/mypyc/lib-rt/base64/config.h b/mypyc/lib-rt/base64/config.h
index fd516c4be2d6..b5e47fb04e75 100644
--- a/mypyc/lib-rt/base64/config.h
+++ b/mypyc/lib-rt/base64/config.h
@@ -7,7 +7,12 @@
 #define BASE64_WITH_SSE41 0
 #define HAVE_SSE41 BASE64_WITH_SSE41
 
+#if defined(__x86_64__) || defined(_M_X64)
+#define BASE64_WITH_SSE42 1
+#else
 #define BASE64_WITH_SSE42 0
+#endif
+
 #define HAVE_SSE42 BASE64_WITH_SSE42
 
 #define BASE64_WITH_AVX 0
diff --git a/mypyc/lib-rt/setup.py b/mypyc/lib-rt/setup.py
index acd61458e516..6a56c65306ae 100644
--- a/mypyc/lib-rt/setup.py
+++ b/mypyc/lib-rt/setup.py
@@ -6,6 +6,7 @@
 from __future__ import annotations
 
 import os
+import platform
 import subprocess
 import sys
 from distutils import ccompiler, sysconfig
@@ -24,6 +25,8 @@
     "pythonsupport.c",
 ]
 
+X86_64 = platform.machine() in ("x86_64", "AMD64", "amd64")
+
 
 class BuildExtGtest(build_ext):
     def get_library_names(self) -> list[str]:
@@ -79,8 +82,12 @@ def run(self) -> None:
     cflags: list[str] = []
     if compiler.compiler_type == "unix":
         cflags += ["-O3"]
+        if X86_64:
+            cflags.append("-msse4.2")  # Enable SIMD (see also mypyc/build.py)
     elif compiler.compiler_type == "msvc":
         cflags += ["/O2"]
+        if X86_64:
+            cflags.append("/arch:SSE4.2")  # Enable SIMD (see also mypyc/build.py)
 
     setup(
         ext_modules=[