Mukesh was born to famous theater artist and writer O. Madhavan and Vijayakumari, who is also an accomplished actress. He was married to famous South Indian film actress Saritha but the coupled filed divorce in 2007.

Mukesh began his career through the movie Balloon in 1982. In 1985, he acted in Mutharamkunnu P. O. directed by Sibi Malayil, with a script by Sreenivasan and story by Jagadeesh. Then came a series of slapstick comedies, often with Priyadarshan, like Ponnum Kudathinu Pottu, Akkare Ninnoru Maran, Boeing Boeing and Odaruthammava Aalariyaam. His breakthrough came in 1989 with the movie Ramji Rao Speaking directed by Siddique-Lal. Thereafter he established himself as a leading actor in the Malayalam film industry. In the early nineties Mukesh acted alongside Jayaram, Jagadeesh and Siddique in a number of low-budget comedy movies. His major hits were directed by duo Siddique-Lal. Apart from Ramji Rao Speaking, they worked together in In Harihar Nagar, Godfather, Hitler, Chronic Bachelor and Friends. The characters he played were usually of a young man doing something fraudulent under the pressure of circumstances. The best example of a film with such a character is Sipayi Lahala (1995) by Vinayan and written by Sreenivasan.

His roles as a supporting actor with Mammootty were acclaimed in hit movies such as Thaniyavarthanam, Dinarathrangal, Mahayanam, Hitler, Chronic Bachelor, Nair Saab, Sainyam and Sangham. He portrayed the CBI officer Chacko in the four movies of the CBI series directed by K. Madhu. He reportedly maintains a close friendship with Mohanlal and has acted with him in movies such as Hello My Dear: Wrong Number, Thalavattam, Vandanam, Akkare Akkare Akkare, Kakkakuyil and Boeing Boeing. In the 2000s he struggled a bit to escape an image trap. He has come back strongly with interesting supporting roles in Udayananu Tharam, Goal, Vinodayathra, Boy Friend, Kaiyoppu, Naalu Pennungal and Katha Parayumbol. He has been a part of many of Mohanlal’s comedies, most of them directed by Priyadarshan.

Apart from acting, he also ventured into production with Sreenivasan. Their first movie, Katha Parayumbol, featured a cameo by Mammootty and was the biggest hit of the year. Mukesh was the host of Kodeeswaran, a television program along the lines of Kaun Banega Crorepati which was aired on Surya TV and was a big success. Mukesh authored and published a book on his reminiscences and anecdotes from life. This book, in the Malayalam language, is titled Mukesh Kathakal – Jeevithathiley Nerum Narmavum. It is a collection of Mukesh’s humorous experiences while he was a student at S. N. College, Kollam, and also contains some tales from his life as a movie actor. The book was a big hit.

Mukesh started Kalidasa Visual Magic for play productions. His first play was with Mohanlal and was named Chayamukhi. In the play, Mukesh played the role of Keechaka and Lal played Bheema.