Mahesh was born on 9 August 1975 in Chennai, Tamil Nadu, India. He was the fourth of the five children of Telugu actor Krishna and Indira, succeeding Ghattamaneni Ramesh Babu, Padmavathi and Manjula Swaroop and preceding Priyadarshini. Mahesh's childhood was spent mostly in Chennai under the care of his maternal grandmother Durgamma and the rest of his family. Since Krishna was busy with his film commitments, Ramesh used to look after Mahesh's academic performance. Along with his siblings, Mahesh used to play cricket regularly at the VGP Golden beach in Chennai. To spend time with him, Krishna used to make sure that his films' shoots would be conducted at the VGP Universal Kingdom during the weekends.
Krishna also made sure that none of his children would reveal his name during their schooling to ensure a peaceful environment. He was educated at St. Bede's Anglo Indian Higher Secondary School in Chennai where actor Karthi was his schoolmate. Mahesh was an above average student. He obtained a bachelor's degree in commerce from Loyola College in Chennai. After graduating, he met with director L. Satyanand in Vishakhapatnam for further training in acting which went on for three to four months. Being unable to read and write Telugu, he used to memorise the dialogues given by his directors during the dubbing phase of his films.
At the age of four, Mahesh visited the sets of the Telugu film Needa (1979) where its director Dasari Narayana Rao shot a few sequences of his as a part of the narrative in the presence of the former's brother Ramesh. Needa marked his debut as a child actor. During the shoot of Poratam (1983) at Vauhini Studios, after watching Mahesh on the sets director Kodi Ramakrishna suggested to Krishna that he cast Mahesh in the role of the protagonist's brother. Initially terrified, Mahesh agreed to act in the film after being persuaded by the film's crew. He went on to act as a child artist in the films Shankharavam (1987), Bazaar Rowdy (1988), Mugguru Kodukulu (1988) and Gudachari 117 (1989). He played a dual role in the film Koduku Diddina Kapuram (1989). Mahesh then appeared in Bala Chandrudu (1990), and Anna Thammudu (1990). Later, Mahesh continued his college studies.
In 1999, Mahesh made his debut as a lead actor with the film Raja Kumarudu, directed by K. Raghavendra Rao and co-starring Priety Zinta. The film was commercially successful, and people began referring to him with the title Prince. He received the Nandi Award for Best Male Debut. He starred in two films the following year – Yuvaraju and Vamsi. Following their poor performance at the box office, Mahesh starred in Krishna Vamsi's Murari the next year. Mahesh called Murari an important film in his career and the role he played in it one of his favourites. Murari was a commercial success and earned him the Nandi Special Jury Award. Though his 2002 releases Takkari Donga and Bobby performed poorly at the box office, Mahesh received his second Nandi Special Jury Award for his performance in the former.
Mahesh had two film releases in 2003, the first one being Gunasekhar's Okkadu co-starring Bhumika Chawla, which went on to become the highest grossing Telugu film of the year. He won his first Filmfare award for best Telugu actor for his performance in the film. The other release was Teja's Nijam co-starring Rakshita. The film was noted for introducing Dolby EX surround system in Telugu cinema. Though the film was a commercial failure, Mahesh received praise from the critics for his performance in the film, with Vijayalaxmi of Rediff.com calling him the only reason to watch the film's second half which she termed a routine tale of vendetta. Mahesh won his first Nandi Best Actor Award for his performance in the film.
Mahesh collaborated with Koratala Siva for the family drama film Srimanthudu co-starring Shruti Haasan. He co-produced the film under his newly formed banner G. Mahesh Babu Entertainment Pvt. Ltd, marking his first film production venture. He opted to do so in order to control the film's budget, accepting a share in profits in lieu of remuneration. Released on 7 August 2015, Srimanthudu opened to positive reviews from the critics, was commercially successful, and gained the best Telugu actor award at the 63rd Filmfare Awards South for Mahesh, marking his resurgence. Sethumadhavan N. of Bangalore Mirror stated, Srimanthudu wouldn't have been as effective if it did not have Mahesh Babu who is at his charming best", adding that he "underplays the emotional scenes, making them a treat to watch".
The Film was a commercial success, grossing nearly ₹2.0 billion globally on a budget of ₹400—700 million and becoming the second-highest grossing Telugu film of all time and the highest grossing Telugu-language-only movie. After the film's release, many actors, bureaucrats and politicians announced plans to develop the backward villages and encouraged the adoption of villages in Telangana and Andhra Pradesh. Mahesh himself has adopted his native village, Burripalem.
Mahesh acted in Srikanth Addala's Telugu family drama film Brahmotsavam co-starring Samantha Ruth Prabhu, Kajal Aggarwal, and Pranitha Subhash. Originally produced as a bi-lingual, the film would've marked Mahesh's first straight Tamil film. However, later on the plan was altered due to its disastrous performance at the Telugu box office and the film wasn't released in Tamil. While the film underperformed at the Boxoffice, the Deccan Chronicle stated that Mahesh Babu was its saving grace. The film was criticized by the public, due to the lack of a proper story. Mahesh stated that this was an error of judgement, where he had picked the wrong director. Mahesh is currently working on Spyder, directed by A. R. Murugadoss, which is going to be Mahesh's 23rd movie as lead actor, and his first bilingual movie which finally marks his first Tamil film. He has signed to do movies with Puri Jagannath and Vamsi. He has also signed to do a movie with director Koratala Siva.