Ed's grandma has never made an appearance, however she is referred to many time in the Tutorials series. Her relationship with Grandpa seems poor.
The first time anyone has made a reference to her was in the Turkey Tutorial. In this episode we find out she gave Ed the recliner that he used in many of his tutorials, which Ed later sabotages to make the beard for Santy Claus in one of his tutorial videos.
The only time she contacts Ed is through various letters. One letter that she sent to Ed contained graphical content, although the footage seems to have been lost.