diff --git a/mypyc/build_setup.py b/mypyc/build_setup.py
index a3e7a669abee..328518e220d6 100644
--- a/mypyc/build_setup.py
+++ b/mypyc/build_setup.py
@@ -1,3 +1,4 @@
+import os
 import platform
 import sys
 
@@ -30,32 +31,41 @@
 
 ccompiler.CCompiler.__spawn = ccompiler.CCompiler.spawn  # type: ignore[attr-defined]
 X86_64 = platform.machine() in ("x86_64", "AMD64", "amd64")
+PYODIDE = "PYODIDE" in os.environ
 
 
 def spawn(self, cmd, **kwargs) -> None:  # type: ignore[no-untyped-def]
-    compiler_type: str = self.compiler_type
-    extra_options = EXTRA_FLAGS_PER_COMPILER_TYPE_PER_PATH_COMPONENT[compiler_type]
-    new_cmd = list(cmd)
-    if X86_64 and extra_options is not None:
-        # filenames are closer to the end of command line
+    if PYODIDE:
+        new_cmd = list(cmd)
         for argument in reversed(new_cmd):
-            # Check if the matching argument contains a source filename.
             if not str(argument).endswith(".c"):
                 continue
+            if "base64/arch/" in str(argument):
+                new_cmd.extend(["-msimd128"])
+    else:
+        compiler_type: str = self.compiler_type
+        extra_options = EXTRA_FLAGS_PER_COMPILER_TYPE_PER_PATH_COMPONENT[compiler_type]
+        new_cmd = list(cmd)
+        if X86_64 and extra_options is not None:
+            # filenames are closer to the end of command line
+            for argument in reversed(new_cmd):
+                # Check if the matching argument contains a source filename.
+                if not str(argument).endswith(".c"):
+                    continue
 
-            for path in extra_options.keys():
-                if path in str(argument):
-                    if compiler_type == "bcpp":
-                        compiler = new_cmd.pop()
-                        # Borland accepts a source file name at the end,
-                        # insert the options before it
-                        new_cmd.extend(extra_options[path])
-                        new_cmd.append(compiler)
-                    else:
-                        new_cmd.extend(extra_options[path])
-
-                    # path component is found, no need to search any further
-                    break
+                for path in extra_options.keys():
+                    if path in str(argument):
+                        if compiler_type == "bcpp":
+                            compiler = new_cmd.pop()
+                            # Borland accepts a source file name at the end,
+                            # insert the options before it
+                            new_cmd.extend(extra_options[path])
+                            new_cmd.append(compiler)
+                        else:
+                            new_cmd.extend(extra_options[path])
+
+                        # path component is found, no need to search any further
+                        break
     self.__spawn(new_cmd, **kwargs)
 
 
diff --git a/mypyc/lib-rt/base64/arch/neon64/codec.c b/mypyc/lib-rt/base64/arch/neon64/codec.c
index 70dc463de94f..72f136f67b8a 100644
--- a/mypyc/lib-rt/base64/arch/neon64/codec.c
+++ b/mypyc/lib-rt/base64/arch/neon64/codec.c
@@ -12,7 +12,7 @@
 #include <arm_neon.h>
 
 // Only enable inline assembly on supported compilers.
-#if defined(__GNUC__) || defined(__clang__)
+#if !defined(__wasm__) && (defined(__GNUC__) || defined(__clang__))
 #define BASE64_NEON64_USE_ASM
 #endif
 
diff --git a/mypyc/lib-rt/base64/config.h b/mypyc/lib-rt/base64/config.h
index 467a722c2f11..8517c7b87d8c 100644
--- a/mypyc/lib-rt/base64/config.h
+++ b/mypyc/lib-rt/base64/config.h
@@ -13,7 +13,7 @@
 #define BASE64_WITH_NEON32 0
 #define HAVE_NEON32 BASE64_WITH_NEON32
 
-#if defined(__APPLE__) && defined(__aarch64__)
+#if (defined(__APPLE__) && defined(__aarch64__)) || (defined(__wasm__) && defined(__wasm_simd128__))
 #define BASE64_WITH_NEON64 1
 #else
 #define BASE64_WITH_NEON64 0
diff --git a/mypyc/lib-rt/setup.py b/mypyc/lib-rt/setup.py
index 5f71d332229c..1030ce496ccd 100644
--- a/mypyc/lib-rt/setup.py
+++ b/mypyc/lib-rt/setup.py
@@ -42,32 +42,41 @@
 
 ccompiler.CCompiler.__spawn = ccompiler.CCompiler.spawn  # type: ignore[attr-defined]
 X86_64 = platform.machine() in ("x86_64", "AMD64", "amd64")
+PYODIDE = "PYODIDE" in os.environ
 
 
 def spawn(self, cmd, **kwargs) -> None:  # type: ignore[no-untyped-def]
-    compiler_type: str = self.compiler_type
-    extra_options = EXTRA_FLAGS_PER_COMPILER_TYPE_PER_PATH_COMPONENT[compiler_type]
-    new_cmd = list(cmd)
-    if X86_64 and extra_options is not None:
-        # filenames are closer to the end of command line
+    if PYODIDE:
+        new_cmd = list(cmd)
         for argument in reversed(new_cmd):
-            # Check if the matching argument contains a source filename.
             if not str(argument).endswith(".c"):
                 continue
-
-            for path in extra_options.keys():
-                if path in str(argument):
-                    if compiler_type == "bcpp":
-                        compiler = new_cmd.pop()
-                        # Borland accepts a source file name at the end,
-                        # insert the options before it
-                        new_cmd.extend(extra_options[path])
-                        new_cmd.append(compiler)
-                    else:
-                        new_cmd.extend(extra_options[path])
-
-                    # path component is found, no need to search any further
-                    break
+            if "base64/arch/" in str(argument):
+                new_cmd.extend(["-msimd128"])
+    else:
+        compiler_type: str = self.compiler_type
+        extra_options = EXTRA_FLAGS_PER_COMPILER_TYPE_PER_PATH_COMPONENT[compiler_type]
+        new_cmd = list(cmd)
+        if X86_64 and extra_options is not None:
+            # filenames are closer to the end of command line
+            for argument in reversed(new_cmd):
+                # Check if the matching argument contains a source filename.
+                if not str(argument).endswith(".c"):
+                    continue
+
+                for path in extra_options.keys():
+                    if path in str(argument):
+                        if compiler_type == "bcpp":
+                            compiler = new_cmd.pop()
+                            # Borland accepts a source file name at the end,
+                            # insert the options before it
+                            new_cmd.extend(extra_options[path])
+                            new_cmd.append(compiler)
+                        else:
+                            new_cmd.extend(extra_options[path])
+
+                        # path component is found, no need to search any further
+                        break
     self.__spawn(new_cmd, **kwargs)