The story revolves around Motu and Patlu, two friends living in Furfuri Nagar. It focuses on how they have a penchant to land in hilarious situations and later rescue themselves by sheer luck. Samosas are the favourite food of Motu. Motu always tries to steal samosas from the local Chaiwala who makes the best samosas in the city. Motu is mainly the black sheep of the duo and creates problems and Patlu always solve it, sometimes Ghasitaram, Chingam and Dr. Jhatka aid them. Sometimes Ghasitaram misdirects and swindles them by making Motu Patlu try Dr. Jhatka's vast repertoire of weird gadgets and gizmos and crazy inventions. When Motu eats samosas, he receives more energy and derives more strength than his normal state.
The main antagonist of the series is a criminal named "John the Don" who is always accompanied by his two dumb henchmen, Number One and Number Two. John intends to become a super criminal of high repute but his plans always tends to fail due to the heroic actions of Motu Patlu, who trap him and expose him and his plans following the strategy of Tit for Tat.