diff --git a/lib/galaxy/app.py b/lib/galaxy/app.py
index 39be835f02ee..7008e4a5e766 100644
--- a/lib/galaxy/app.py
+++ b/lib/galaxy/app.py
@@ -159,7 +159,7 @@ def __init__(self, **kwargs):
         self.datatypes_registry.load_external_metadata_tool(self.toolbox)
         # Load history import/export tools.
         load_lib_tools(self.toolbox)
-        self.toolbox.persist_cache()
+        self.toolbox.persist_cache(register_postfork=True)
         # visualizations registry: associates resources with visualizations, controls how to render
         self.visualizations_registry = VisualizationsRegistry(
             self,
diff --git a/lib/galaxy/tools/__init__.py b/lib/galaxy/tools/__init__.py
index 5330f891d3f5..8b61dfe81373 100644
--- a/lib/galaxy/tools/__init__.py
+++ b/lib/galaxy/tools/__init__.py
@@ -261,9 +261,19 @@ def __init__(self, config_filenames, tool_root_dir, app, save_integrated_tool_pa
             save_integrated_tool_panel=save_integrated_tool_panel,
         )
 
-    def persist_cache(self):
+    def persist_cache(self, register_postfork=False):
+        """
+        Persists any modified tool cache files to disk.
+
+        Set ``register_postfork`` to stop database thread queue,
+        close database connection and register re-open function
+        that re-opens the database after forking.
+        """
         for region in self.cache_regions.values():
             region.persist()
+            if register_postfork:
+                region.close()
+                self.app.application_stack.register_postfork_function(region.reopen_ro)
 
     def can_load_config_file(self, config_filename):
         if config_filename == self.app.config.shed_tool_config_file and not self.app.config.is_set('shed_tool_config_file'):
diff --git a/lib/galaxy/tools/cache.py b/lib/galaxy/tools/cache.py
index 042ae776bfda..37ee95f013a5 100644
--- a/lib/galaxy/tools/cache.py
+++ b/lib/galaxy/tools/cache.py
@@ -43,6 +43,13 @@ def __init__(self, cache_dir):
         # Switch SqliteDict back to readonly
         self._cache.flag = 'r'
 
+    def close(self):
+        self._cache.close()
+
+    def reopen_ro(self):
+        self._cache = SqliteDict(self.cache_file, flag='r', encode=encoder, decode=decoder, autocommit=False)
+        self.writeable_cache_file = None
+
     def get(self, config_file):
         tool_document = self._cache.get(config_file)
         if not tool_document:
@@ -65,8 +72,7 @@ def persist(self):
         if self.writeable_cache_file:
             self._cache.commit()
             os.rename(self.writeable_cache_file.name, self.cache_file)
-            self._cache = SqliteDict(self.cache_file, flag='r', encode=encoder, decode=decoder, autocommit=False)
-            self.writeable_cache_file = None
+            self.reopen_ro()
 
     def set(self, config_file, tool_source):
         self.make_writable()