Muzaffargarh was founded in 1794 by the Governor of Multan Nawab Muzaffar Khan. The meaning of Muzaffargarh is "Fort of Muzaffar" because the old town lies inside the walls of a fort built by Nawab Muzaffar Khan of Multan. Prior to that, the place was known by a shop called "Musan Hatti", on the road leading from Multan to Dera Ghazi Khan. In 1861, it became a District.
After the independence of Pakistan in 1947, the minority Hindus and Sikhs migrated to India while the Muslim refugees from India settled in the Muzaffargarh District. Muslims refugees from East Punjab, Haryana, Jammu started arriving and crossed the border into Pakistan; many were given land in Muzaffargarh district to settle.
Muzaffargarh spreads over an area of 8,249 km2 and forms a strip between the Chenab River on its east and Indus River on its west, which pass along the Eastern and Western boundaries respectively of the district and a triangle at Alipur tehsil of the district. The district is bounded on the north by district Layyah, on the south by Bahawalpur and Rahimyar Khan districts across the river Chenab. District Multan and district Khanewal are on the eastern side of district Muzaffargarh, across the river Chenab. District Jhang touches it on the northeast. Dera Ghazi Khan and Rajanpur districts lie on the western side across the river Indus. According to the 1998 census of Pakistan, the population of the district was 26,35,903 of which 12.75% were urban. Muzaffargarh is one of oldest districts of Punjab. Muzaffargarh was especially hard hit by the 2010 Pakistan floods, given its position between the Chenab and Indus rivers.