A horror-comedy story, Oh my Ghost is about Trixie (Rufa Mae Quinto), a beautiful and sexy ad agency executive who focuses on her career and less of her love life. Even her best friend and partner in the agency, Alvin (Marvin Agustin), tries to make moves on her but just doesn't work. Meanwhile, three young egotistic guys - Dennis (Paolo Contis), Jeff (Carlos Agassi) and Buboy (Uma Khouny), meet Trixie in the gym who get so attracted and madly in love with her. Because of their arrogance and conceitedness, Trixie turns each one down that makes the three angry at her. To get even with her, they attempt to rape her that lead to a fatal accident. So sudden and untimely, Trixie's ghost cannot accept it and decides to take revenge. Horror-comic situations follow as she haunts the three to obtain justice.

The plot revolves around a secret agency with Reserve Agent King Aguila tasked to recover the Philippines' most important artifact. The artifact is the bolo of Lapu-lapu which he used to kill Magellan in 1521.