Janey and Grandma escape their frigid Michigan hometown for the palm tree lined streets of sunny Los Angeles. Bright-eyed early-twenty-something Janey has always dreamed of becoming an actress so she and her Grandma, a quirky sixty-something with a young heart, pack up and head west where Grandma realizes she too aspires to be famous. Me and My Grandma follows the misadventures of the two best friends as they take on career, hookups, and life in Hollywood - all while saving up for a second air mattress.
When Janey is hesitant to leave home and pursue her dream of acting in Hollywood, Grandma convinces her to go by offering to come along for moral support. Once in their shoddy apartment in tinsel town, friction grows between the women but it's not just roommate issues: Grandma scores a role in a commercial over Janey. Fortunately, Janey finds a silver lining when she meets the dreamy Oliver, a fellow Michigander and aspiring director. Her hopes are quickly dashed when an embarrassing accident on the set goes viral and Janey becomes the "Grandma, No!" girl.
Janey's embarrassing viral video turns sweet when the attention lands her and Grandma invites to their first red carpet, an event for digital phenom Gigi Gorgeous. The timing couldn't be better, as Grandma's just discovered the power of social media, and has decided to make a go at digital success herself. At the premiere, joined by Heidi and her younger brother Hank, the duo try to network like true Hollywood types but an incident in the gift suite squashes their hopes of making a good impression.
To pay for quality headshots, Grandma and Janey set up a bake sale next to a dispensary at Venice Beach. Hell breaks loose when Grandma accidentally gets too stoned and gets arrested by a handsome bike cop named Desmond. Meanwhile, Janey gets her first chance to prove her acting prowess when she's called in to audition for Oliver's movie.
When Janey and Victoria clash on the set of Oliver's film, he suggests they bond. Janey invites Victoria to join her and Grandma as they help with Heidi's experimental art show. Oliver is so impressed with Heidi's skills he offers her a job on his movie, while Grandma meets an attractive older gentleman.
Janey struggles with the knowledge of Victoria's secret, despite Grandma's advice to let it go. Grandma's finally gotten a check from the car commercial, and the girls can finally move out of The Ass. On the set of Oliver's movie, Heidi excels at the makeup but Grandma and Janey argue about the men in their lives. An earthquake throws everything into focus when Grandma gets stuck in a porta potty and Janey and Oliver finally talk.
All of the drama in Janey and Grandma's lives comes to a head while they are attending the premiere party for Oliver's film.
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