Namisindwa District is bordered by Bududa District to the north, Kenya to the east and south, Tororo District to the south-west, and Manafwa District to the west. The district headquarters at Bupoto are located approximately 40 kilometres (25 mi), by road, south-east of Mbale, the largest city of in the sub-region.
Namisindwa District became operational on 1 July 2017. Prior to that the new district was "East Bubulo County" in Manafwa District. The rationale for creating the new district was (a) to bring services closer to the people and (b) create jobs and reduce youth unemployment.
As of August 2015, the district had 80 schools. The district terrain in described as "hilly", and prone to soil erosion during the rainy season. The gravel roads need frequent maintenance. The Bumbobi–Bubulo–Lwakhakha Road traverses the district in a general northwest to southeast direction.