Paleolithic man probably roamed around the areas of lower Godavari valley[2] and the surroundings of Wyra, Sathupalli Taluks in the district.

Prehistoric rock paintings were found near Neeladri konda[3] near Lankapalli of Sathupalli Taluk.

Megalithic site on the campus of Government Degree college in Khammam has yielded pottery and skeletal remains.

The southern parts of Khammam district flourished as famous Buddhist centers along with Amaravathi and Vijayapuri along the rivulets Munneru, Wyra and Murredu.

On 1 November 1956, Hyderabad state was dissolved, and Khammam district became part of Andhra Pradesh.

On 11 July 2014, the Lok Sabha approved a bill transferring seven mandals of Khammam district (Kukunoor, Velairpadu, Bhurgampadu, Chintoor, Kunavaram, Vararamachandrapuram and Bhadrachalam) back to Andhra Pradesh, in order to facilitate the Polavaram Irrigation project.

The mandals of Chinturu, Kunavaram, Nellipaka and Vararamachandrapuram were added to East Godavari district based on Polavaram ordinance.