Mahesh Babu debuted in 1999 with the K. Raghavendra Rao film Raja Kumarudu opposite Preity Zinta, opened well at the box office and is commercially successful whilst earning Mahesh the Nandi Award for Best Male Debut.
In 2000, Mahesh Babu appeared in Y.V.S Chowdary's Yuvaraju,and in Vamsi. Both movies were declared average at the box office.
In 2001, he starred with Sonali Bendre in Krishna Vamsi's Murari, which emerged as a critical as well as a huge commercial success. His performance earned him the Nandi Special Jury Award. His next movie Takkari Donga opened to positive reviews. Mahesh's performance earned him the Nandi Special Jury Award.
Later that year, he starred with Arthi Agarwal in Bobby, directed by Sobhan. The movie was commercially unsuccessful at the box-office.
His next film Okkadu (2003) opposite Bhumika Chawla, produced by M.S. Raju and directed by Gunasekhar was critically acclaimed and a biggest box-office success of that year whilst earning his first Filmfare Best Actor Award (Telugu). The film collected a share of Indian Rupee ₹ 7 crores in its opening week in Andhra Pradesh. In the same year, he appeared in Teja's film Nijam was critically acclaimed and earned him Nandi Award for Best Actor. In 2004, he paired up with Amisha Patel in S. J. Suryaah's Nani. This was the Telugu version of the Tamil film, New. Later that year, he again appeared in Gunasekhar movie Arjun opposite Shriya Saran did well at the box office and earned him another Nandi Special Jury Award.
His 2005 film with Trisha Krishnan, titled Athadu directed by Trivikram Srinivas was declared sensational hit in india as well as in USA and became one of the highest grossers of the year in tollywood and his performance earned him second Nandi Award for Best Actor. He next appeared opposite Ileana D'Cruz in the action flick Pokiri (2006) directed and produced by Puri Jagannath is a critically acclaimed and all time Telugu film Industry record hit. The film was a huge financial success, emerging the highest grossing Telugu film of all time in the year 2006 with Indian Rupee ₹ 66.5 Crores. The film completed 100 days in as many as 200 centres in the andhra pradesh and neighbouring States, including 17 centers in Hyderabad alone and silver jubilee in a record 63 centres. In the same year, he again starred with Trisha in Gunasekhar's film Sainikudu opened well in india, ending up as an average grosser.
In October 2007, he appeared with Amrita Rao in Surender Reddy's Athidhi which was a commercial Hit. The film opened with a gross collection of Indian Rupee ₹ 12.5 crores in the first week of its release.
He next signed a film with Trivikram Srinivas titled Mahesh Khaleja opposite Anushka Shetty. Mahesh Babu had planned to take a gap of six months after Athidhi. Due to unexpected circumstances, the film was postponed several times and took two years to be completed. Khaleja was released on 7 October 2010. The film received mixed reviews. and ended up as an average grosser.
His current film Dookudu by Sreenu Vaitla's is scheduled to release in May 2011, after which he will be working for Puri Jagannath's next venture, tentatively titled The Business Man. He agreed to do a Tamil film Ponniyin Selvan with noted Indian film maker Mani Ratnam, where he likely to play Warrior Aditya Karikalan.