The movie begins with an underworld don Billa (Prabhas), featured on Interpol's criminal list, hiding and operating out of Malaysia. Krishnamoorthy (Krishnam Raju) has spent the last few years looking for Billa, leaving behind a life in India.
Bujji (Prabhas) and Chitti (Trisha Krishnan) are inseparable childhood friends. But when Bujji crashes Chitti's sandcastle by mistake, Chitti gets angry and asks Bujji not to meet her for 12 years. She does, however, promise to marry him at the end of the lengthy hiatus, leaving Bujji but a glimmer of hope. After half-heartedly agreeing to her harsh terms, the forlorn Bujji leaves home, the pain of living in Visakhapatnam without seeing Chitti too much to bear. He winds up in Chennai, hence the tagline, Made in Chennai.
After witnessing the unfortunate death of a woman, who was unable to afford hospital treatment, Dr. Ajay Kumar (Akkineni Nagarjuna) cancels his U.S. immigration and instead sets out to work a plan to open a hospital that will be accessible to people who cannot afford treatment in regular hospitals, called "Amma Hospital".