Index: llvm/include/llvm/IR/InstrTypes.h
===================================================================
--- llvm/include/llvm/IR/InstrTypes.h
+++ llvm/include/llvm/IR/InstrTypes.h
@@ -1391,7 +1391,12 @@
   /// Returns the function called, or null if this is an
   /// indirect function invocation.
   Function *getCalledFunction() const {
-    return dyn_cast_or_null<Function>(getCalledOperand());
+    // With opaque pointers, only consider it a direct call if the declaration
+    // signature matches the call signature.
+    if (auto *F = dyn_cast<Function>(getCalledOperand()))
+      if (F->getValueType() == getFunctionType())
+        return F;
+    return nullptr;
   }
 
   /// Return true if the callsite is an indirect call.
Index: llvm/test/Transforms/InstSimplify/known-non-zero-opaque-ptrs.ll
===================================================================
--- /dev/null
+++ llvm/test/Transforms/InstSimplify/known-non-zero-opaque-ptrs.ll
@@ -0,0 +1,51 @@
+; NOTE: Assertions have been autogenerated by utils/update_test_checks.py
+; RUN: opt -S -instsimplify -force-opaque-pointers < %s | FileCheck %s
+
+declare void @zero_args()
+declare void @two_args(ptr, ptr)
+
+; TODO: Could be non-null based on call-site attributes.
+define i1 @test_zero_args_nonnull(ptr %p) {
+; CHECK-LABEL: @test_zero_args_nonnull(
+; CHECK-NEXT:    call void @zero_args(ptr noundef nonnull [[P:%.*]])
+; CHECK-NEXT:    [[C:%.*]] = icmp ne ptr [[P]], null
+; CHECK-NEXT:    ret i1 [[C]]
+;
+  call void @zero_args(ptr nonnull noundef %p)
+  %c = icmp ne ptr %p, null
+  ret i1 %c
+}
+
+define i1 @test_zero_args_maybe_null(ptr %p) {
+; CHECK-LABEL: @test_zero_args_maybe_null(
+; CHECK-NEXT:    call void @zero_args(ptr [[P:%.*]])
+; CHECK-NEXT:    [[C:%.*]] = icmp ne ptr [[P]], null
+; CHECK-NEXT:    ret i1 [[C]]
+;
+  call void @zero_args(ptr %p)
+  %c = icmp ne ptr %p, null
+  ret i1 %c
+}
+
+; TODO: Could be non-null based on call-site attributes.
+define i1 @test_two_args_nonnull(ptr %p) {
+; CHECK-LABEL: @test_two_args_nonnull(
+; CHECK-NEXT:    call void @two_args(ptr noundef nonnull [[P:%.*]])
+; CHECK-NEXT:    [[C:%.*]] = icmp ne ptr [[P]], null
+; CHECK-NEXT:    ret i1 [[C]]
+;
+  call void @two_args(ptr nonnull noundef %p)
+  %c = icmp ne ptr %p, null
+  ret i1 %c
+}
+
+define i1 @test_two_args_maybe_null(ptr %p) {
+; CHECK-LABEL: @test_two_args_maybe_null(
+; CHECK-NEXT:    call void @two_args(ptr [[P:%.*]])
+; CHECK-NEXT:    [[C:%.*]] = icmp ne ptr [[P]], null
+; CHECK-NEXT:    ret i1 [[C]]
+;
+  call void @two_args(ptr %p)
+  %c = icmp ne ptr %p, null
+  ret i1 %c
+}