A native of Tamil Nadu, Prabhu was born to Sivaji and Kamala Ganesan. He has an elder brother Ramkumar Ganesan who is a film producer, and two sisters, Shanthi and Thenmozhi. He did his schooling at Bishop Cotton Boys’ School in Bangalore. He later pursued a BA in History at Loyola College, Chennai. He was active in sports. He dropped out from Loyola in his second year. He married Punitha in 1981. They have a son Vikram Prabhu and a daughter Aishwarya Prabhu. In 2011 Prabhu was conferred with an honorary doctorate by the Sathyabama University.
After making his debut in the film Sangili in 1982, he has acted in over 150 films. In the beginning, Ganesan frequently appeared alongside other actors like Rajinikanth, Kamal Hassan, and his father Sivaji Ganesan. He received the Tamil Nadu State Film Award for Best Actor in 1991 for his performance in Chinna Thambi. In 2000 Prabhu appeared in Suyamvaram, which was shot with in 24 hours with an extensive cast. He appeared alongside Rajinikanth in Guru Sishyan and Dharmathin Thalaivan (both 1988) and Chandramukhi in 2005, and in Vetri Vizha (1989) and Vasool Raja MBBS (2004) with Kamal Haasan. He starred as a cop operating in Malaysia in Billa in 2007. In 2008 Prabhu acted in Kuselan, Silambattam and Ayan playing supporting roles in all films, and in Mani Ratnam’s Raavanan, and Maanja Velu. When his fellow colleagues refused to take up the role of Trisha’s brother in Unakkum Enakkum, Prabhu took up the role. He appeared with Vishal in Thamirabarani and Thambikku Indha Ooru with Bharath.
Prabhu made his Telugu language debut in Orange where he acted alongside Ram Charan Tej. He acted in two Malayalam films—Pramaani and Best of Luck, followed by the Telugu film Darling. In 2011 Prabhu made his Kannada language debut through Boss with Darshan as the hero. Prabhu plays a cop in the film.
Prabhu has acted over 150 films in Tamil, Telugu, Kannada, Malayalam and English (Ele My Friend). His notable achievements: 46 movies crossed 100 days, 5 movies crossed 175 days and 3 movies crossed 200 Days. Chinna Thambi is the only movie that has crossed 200 days in 9 screens, 100 days in 67 screens with 4 daily shows till date in Tamil Cine Industry. The movie has grossed over 10 Crores revenue in 90’s and broken all the Tamil Film industry records before to that.