Acute kidney injury is strongly associated with mortality in COVID-19 patients. However, host cell changes underlying infection of kidney cells with SARS-CoV-2 remain unknown and prevent understanding of the mechanisms leading to renal pathology. Here, we carried out extensive, dual-level proteomic analyses of primary human kidney cells infected with SARS-CoV-2 or MERS-CoV to disseminate virus and cell type specific changes. We established cellular infection models of proximal and distal tubular epithelial cells derived from human donors. Infected cells were analyzed by quantitative translatome and whole-cell proteomics over time. Our findings reveal shared pathways modified upon infection with both viruses, as well as SARS-CoV-2 specific host cell modulation driving key changes in innate immune activation, cellular protein quality control and mitochondrial biology. In addition, we identified extensive modulation in pathways associated with kidney failure that were instinctively regulated in a virus- and cell type-specific manner. Our findings provide an overview of the effects of SARS-CoV-2 or MERS-CoV infection on primary kidney cells revealing key pathways and highlighting potential treatment options.