diff --git a/conan/internal/api/profile/profile_loader.py b/conan/internal/api/profile/profile_loader.py
index 097092b760c..d1e422c7a77 100644
--- a/conan/internal/api/profile/profile_loader.py
+++ b/conan/internal/api/profile/profile_loader.py
@@ -348,6 +348,8 @@ def get_package_name_value(item):
             result_name, result_value = item.split("=", 1)
             result_name = result_name.strip()
             result_value = _unquote(result_value)
+            if result_value == "~":  # Can be used to undefine an already defined setting
+                result_value = None
             return packagename, result_name, result_value
 
         package_settings = OrderedDict()
@@ -388,6 +390,8 @@ def _get_simple_and_package_tuples(items):
         package_items = defaultdict(list)
         tuples = _get_tuples_list_from_extender_arg(items)
         for name, value in tuples:
+            if value == "~":  # Can be used to undefine an already defined setting
+                value = None
             if ":" in name:  # Scoped items
                 tmp = name.split(":", 1)
                 ref_name = tmp[0]
diff --git a/test/integration/configuration/profile_test.py b/test/integration/configuration/profile_test.py
index f031fded2cd..ac7ce1b563f 100644
--- a/test/integration/configuration/profile_test.py
+++ b/test/integration/configuration/profile_test.py
@@ -6,7 +6,6 @@
 from textwrap import dedent
 
 import pytest
-from parameterized import parameterized
 
 from conan.internal.paths import CONANFILE
 from conan.test.assets.genconanfile import GenConanfile
@@ -645,3 +644,33 @@ def test_compose_numeric_values_scoped_pkg():
 
     tc.run("create . -pr=profile")
     assert "user.var.value: 10" in tc.out
+
+
+def test_nullify_settings():
+    c = TestClient()
+    conanfile = textwrap.dedent("""
+        from conan import ConanFile
+        class Pkg(ConanFile):
+            settings = "build_type"
+            def configure(self):
+                if not self.settings.build_type:
+                    self.output.info("BUILD TYPE NOT DEFINED!!!")
+                else:
+                    self.output.info(f"I am a {self.settings.build_type} pkg!!!")
+        """)
+    c.save({"conanfile.py": conanfile,
+            "profile": "[settings]\nbuild_type=Release\npkg1/*:build_type=~"})
+    c.run("create . --name=pkg1 --version=0.1")
+    c.run("create . --name=pkg2 --version=0.1")
+    c.run("create . --name=pkg3 --version=0.1")
+    c.save({"conanfile.py": GenConanfile().with_requires("pkg1/0.1", "pkg2/0.1", "pkg3/0.1")})
+
+    c.run("graph info . -s build_type=Release -s pkg1/*:build_type=~")
+    assert "pkg1/0.1: BUILD TYPE NOT DEFINED!!!" in c.out
+    assert "pkg2/0.1: I am a Release pkg!!!" in c.out
+    assert "pkg3/0.1: I am a Release pkg!!!" in c.out
+
+    c.run("graph info . -pr=profile")
+    assert "pkg1/0.1: BUILD TYPE NOT DEFINED!!!" in c.out
+    assert "pkg2/0.1: I am a Release pkg!!!" in c.out
+    assert "pkg3/0.1: I am a Release pkg!!!" in c.out