Speaking to BBC Radio 1, the comedian and actor said it would be wrong to carry on with the BBC Two sitcom.
Asked by breakfast show host Nick Grimshaw if a third series was on the way, Amstell said: "No… We felt we'd written all the pain out of us. It would be sort of gratuitous to keep going.
"Also, I sort of leave things once I know how to do them and they've become good, which is upsetting I think for the public because it would be nice if I could just keep [going]."
He added: "I worry, 'Right, they've started liking this; let's get out of here before it turns to hate!'"
Grandma's House ran for 12 episodes over its two series, and starred Linda Bassett, Geoffrey Hutchings, Rebecca Front, James Smith and Samantha Spiro alongside Amstell.
The show was co-created and written by Amstell and Dan Swimer.
Watch a clip from the final episode of Grandma's House below: