A misfit, as the word implies, is someone who doesn't fit in with a group. The man called the Misfit clearly doesn't fit into society at large, as he is an escaped convict and a murderer. But the grandmother also doesn't fit in. In her case, she doesn't fit well with her family group, making her a misfit on a smaller scale.
First, the grandmother wants to go to Tennessee for vacation, while the rest of the family wants to go to Florida. Second, when she repeatedly comes up with reasons not to go to Florida, her son and daughter-in-law simply ignore her as if she is not there, and her grandson, John Wesley, says:
If you don’t want to go to Florida, why dontcha stay at home?
The granddaughter, June Star, is also rude to her: it becomes clear the grandmother has only been invited along because the family feels obligated to bring her, not because she's wanted. At the Tower, when she asks Bailey to dance, he "glares" at her without responding, suggesting he is already fed up with her. Even her luggage doesn't fit well into the car, so that it is finally her cat jumping out a basket that causes the accident that leads to the bad ending.
The grandmother's depiction in the story shows us several ways we can identify a misfit: her presence is tolerated rather than wanted, she gets on her children's and grandchildren's nerves, often what she says is ignored, and her needs are not seen as important.
Being a misfit doesn't necessarily make someone a bad person: there are groups we fit in and groups we don't. Not everyone is going to be comfortable or accepted everywhere. We see how much better the grandmother fits in with Red Sam, for example, who actually appreciates talking to her.