Kidney clear cell carcinoma (KIRC) is a prevalent urological cancer. Despite substantial improvements in KIRC care, patients with intermediate and advanced stages of the disease lack access to appropriate medications. Doxorubicin is widely used as a chemotherapy drug for the treatment of multiple types of cancer. However, its use is associated with harmful side effects and drug resistance. ErbB3-binding protein (EBP1) is highly expressed in KIRC, and the knockdown of EBP1 reduces the phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and the expression of HIF-1α. Therefore, the present study aimed to evaluate the effectiveness of combined doxorubicin administration and EBP1 knockdown in KIRC cell lines. The KIRC cell lines 786-O and 769-P were used for the experiments, and short hairpin RNA technology was employed to specifically knock down the expression of the EBP1 gene. After treatment, cells were analyzed by western blotting to detect changes in p38MAPK phosphorylation levels and HIF-1α expression. The results showed that EBP1 knockdown significantly enhanced the antitumor effect of doxorubicin on KIRC cells through the p38MAPK/HIF-1α pathway. In conclusion, the knockdown of EBP1 in combination with doxorubicin may be a potential strategy for the treatment of KIRC.