Hypoxia-inducible factor (HIF) is a transcription factor that regulates cellular hypoxic responses. Despite the therapeutic benefits of cyclosporine A (CsA) in organ transplantation, its clinical use is limited due to chronic nephropathy. We investigated whether HIF activation by cobalt could improve CsA-induced nephropathy, and investigated the related mechanism. In animal experiments, rats were kept on a 0.05% low-salt diet and administered CsA subcutaneously for 28 days (15 mg/kg/day). They also received cobalt (10 mg/kg/day) during the entire experimental period. The administration of cobalt significantly increased HIF-1α expression in the kidney. The increased expression of HIF-1α ameliorated CsA-induced afferent arteriolopathy and tubulointerstitial injury in the kidney. Cobalt significantly reduced the infiltration of macrophages/monocytes into the renal tubulointerstitium. In addition, HIF activation by cobalt reduced the number of CsA-induced apoptotic cells in the kidney. Subsequently, HK-2 human renal tubular epithelial cells were used for in vitro experiments. They were pre-treated with 150 µM of cobalt to activate HIF, and then exposed to 10 µM CsA. HIF activation by cobalt decreased the CsA-induced apoptosis in HK-2 cells, as judged by the decreases in the number of apoptotic cells, pro-apoptotic caspase-3 activity, and the expression level of cleaved caspase-3, together with the increase in the expression of anti-apoptotic bcl-2. Cobalt pretreatment also reduced the CsA-induced phosphorylation of NF-κB and the CsA-induced expression of vimentin and α-smooth muscle actin, suggesting the attenuation of inflammation and fibrosis. In conclusion, the activation of HIF by cobalt may ameliorate the CsA-induced nephropathy by inhibiting apoptosis, inflammation, and fibrosis.