PRISCILLA follows the journey of two drag queens, Tick and Adam, and a transgender woman, Bernadette, as they travel across Australia in their bus, named Priscilla. Tick has been asked to perform at a hotel in Alice Springs by his estranged wife, Marion. Taking Adam and Bernadette along with him, the trio drive from Sydney to the remote resort town in the middle of the desert. Tick tells his companions that the trip is a favour to his wife, from whom he is separated, but does not reveal that he also has an 8-year-old son he does not know, but who now wants to meet his father.

As they head west, Tick, Adam, and Bernadette learn to accept and support each other, whilst encountering a number of strange and colourful characters. After experiencing violent homophobic threats, Adam is forced to realise that not everyone is accepting of his flamboyant lifestyle, whilst Bernadette opens up to the possibility of love again following the death of her husband