The name of the district came from nong which means ‘wetland‘ and khaem which means ‘reed’ (Phragmites karka), a reedy plant, reflecting its environment in the past. It was set up as Amphoe Nong Khaem in 1902. In 1938 it become a king amphoe of Amphoe Phasi Charoen for about 20 years before it was elevated to amphoe status again. It became a khet in 1972 after Bangkok administrative reform. In 1998, the eastern part of Nong Khaem (Lak Song Sub-district) was made part of the newly established district of Khet Bang Khae.
In 1973 Thai President Foods started production of its instant food in a factory in Nong Khang Phlu, most notably the instant noodle soup of the MAMA brand. In 1986 the factory was moved to Si Racha, as the old one became too small.