diff --git a/netbox/dcim/forms/model_forms.py b/netbox/dcim/forms/model_forms.py
index 9bc69e991c7..5a3a27d25e8 100644
--- a/netbox/dcim/forms/model_forms.py
+++ b/netbox/dcim/forms/model_forms.py
@@ -1810,6 +1810,11 @@ def __init__(self, *args, **kwargs):
 
         super().__init__(*args, **kwargs)
 
+        if instance and instance.assigned_object and instance.assigned_object.primary_mac_address:
+            if instance.assigned_object.primary_mac_address.pk == instance.pk:
+                self.fields['interface'].disabled = True
+                self.fields['vminterface'].disabled = True
+
     def clean(self):
         super().clean()
 
diff --git a/netbox/dcim/models/devices.py b/netbox/dcim/models/devices.py
index dbcd91ea0ed..6ef5ab48893 100644
--- a/netbox/dcim/models/devices.py
+++ b/netbox/dcim/models/devices.py
@@ -15,6 +15,7 @@
 from django.utils.safestring import mark_safe
 from django.utils.translation import gettext_lazy as _
 
+from core.models import ObjectType
 from dcim.choices import *
 from dcim.constants import *
 from dcim.fields import MACAddressField
@@ -1522,3 +1523,27 @@ class Meta:
 
     def __str__(self):
         return str(self.mac_address)
+
+    def __init__(self, *args, **kwargs):
+        super().__init__(*args, **kwargs)
+
+        # Denote the original assigned object (if any) for validation in clean()
+        self._original_assigned_object_id = self.__dict__.get('assigned_object_id')
+        self._original_assigned_object_type_id = self.__dict__.get('assigned_object_type_id')
+
+    def clean(self, *args, **kwargs):
+        super().clean()
+        if self._original_assigned_object_id and self._original_assigned_object_type_id:
+            assigned_object = self.assigned_object
+            ct = ObjectType.objects.get_for_id(self._original_assigned_object_type_id)
+            original_assigned_object = ct.get_object_for_this_type(pk=self._original_assigned_object_id)
+
+            if original_assigned_object.primary_mac_address:
+                if not assigned_object:
+                    raise ValidationError(
+                        _("Cannot unassign MAC Address while it is designated as the primary MAC for an object")
+                    )
+                elif original_assigned_object != assigned_object:
+                    raise ValidationError(
+                        _("Cannot reassign MAC Address while it is designated as the primary MAC for an object")
+                    )