Central Asia (CA) is one of the most fragile regions worldwide owing to arid climate and accumulated human activities, and is a global hotspot due to gradually deteriorating ecological environment. The Amu Darya Basin (ADB), as the most economically and demographically important region in CA, is of particular concern. To determine the concentration, source and pollution status of heavy metals (HMs) in surface sediments of the ADB, 154 samples were collected and analyzed for metals across the basin. Correlation and cluster analysis, and positive matrix factorization model were implemented to understand metals’ association and apportion their possible sources. Cumulative frequency distribution and normalization methods were used to determine the geochemical baseline values (GBVs). Then, various pollution indices and ecological risk index were employed to characterize and evaluate the pollution levels and associated risks based on the GBVs. Results indicated that the mean concentrations of HMs showed the following descending order in the surface sediments of ADB: Zn > Cr > Ni > Cu > Pb > Co > Cd. The spatial distribution maps showed that Cr, Ni, and Cu had relatively high enrichment in the irrigated agricultural area; high abundances of Zn, Pb, and Cd were mainly found in the urban areas. Four source factors were identified for these metals, namely natural sources, industrial discharge, agricultural activities, and mixed source of traffic and mining activities, accounting for 33.5%, 11.4%, 34.2%, and 20.9% of the total contribution, respectively. The GBVs of Cd, Zn, Pb, Cu, Ni, Cr, and Co in the ADB were 0.27, 58.9, 14.6, 20.3, 25.8, 53.4, and 9.80 mg/kg, respectively, which were similar to the regional background values obtained from lake sediments in the bottom. In general, the assessment results revealed that surface sediments of the ADB were moderately polluted and low ecological risk by HMs.