No.20 Madras Mail movie revolves around a train journey in No. 20 Madras Mail. Tony Kurushingal (Mohanlal) along with his friends Hitchcock Kanjikuzhyi (Manianpilla Raju) and Kumbalam Hari (Jagadish) see Mammootty along the way. Tony and friends are attracted to the girl in the next compartment, Devi (Suchitra). They make fun all the way and Tony also lands in trouble with Devi's father, R. K. Nair (M.G. Soman), but is saved by Mammootty.
In the morning, as the train reaches Madras, Devi is found murdered in the toilet. Suspicion lands on Tony and friends. Hunted by the police, they seek Mammootty's help as only he believes in their innocence. The plot follows their attempts to escape and find out who really killed the girl.