Depleted uranium (DU) is an important by product in uranium enrichment process. Due to its applications in civilian and also military activity, DU emerged as environmental pollutant. The exposure to DU can occur via external or internal pathways. In external exposure, mainly beta radiation from the decay products contributes to DU toxicity. Internal exposure to DU is more important and can occur through ingestion of DU-contaminated water and food and inhalation of DU aerosols. There is limited information about health effects and mechanism of DU after environmental exposure. Kidney is reported as the main target organ for the chemical toxicity of this metal that was reported in Persian Gulf syndrome. Alterations in behavior, some neurologic adverse effects, immunotoxicity, embryo-toxicity and hepatotoxicity were observed in chronic exposure to DU. Also, the increased risk of cancer was revealed in epidemiological and experimental studies. Several mechanisms were suggested for DU toxicity such as oxidative stress, mitochondrial toxicity and inflammation. In fact, uranium like other toxic heavy metals can induce oxidative damage and apoptosis via mitochondrial pathway and inflammatory response. In this review, we have discussed the kinetic of DU including source and exposure pathway. In addition, the health effects of DU and also its toxic mechanism have been highlighted.