In recent years, the outbreak of cyanobacterial blooms has become increasingly frequent. Microcystin-LR (MC-LR), a metabolite of cyanobacteria, poses a significant threat to the ecosystem and human health. Several studies have demonstrated that MC-LR might induce renal cell apoptosis, as a consequence of tissue damage. However, the molecular mechanisms underlying MC-LR-initiated renal injury remain to be determined. This investigation aimed to determine the role of apoptosis in MC-LR-induced kidney damage and its potential underlying mechanisms using the human embryonic kidney (HEK293) cell line. The results of TUNEL and immunofluorescence assays indicated that MC-LR induced increased apoptosis in HEK293 cells. Compared to control, the mRNA expression levels of RIPK1, caspase-8, and TNF-α were elevated following incubation with MC-LR, while the mRNA expression level of Bcl-2/Bax was decreased. The protein levels of RIPK1, TNF-R1, and caspase-8 were elevated in the MC-LR-treated HEK293 cells. Data demonstrated that MC-LR induced renal cell apoptosis through activation of the TNF-R1/RIPK1 pathway, providing new insights into understanding the toxic mechanisms attributed to MC-LR.