Introduction: Renal cell carcinoma (RCC) generally has a poor prognosis because of late diagnosis and metastasis. Despite its abundance in RCC cells, the functions of Kallikrein-related peptidase 4 (KLK4) in RCC cells remain unknown. The results of this investigation were examined to discover if KLK4 gene silencing influences the development of RCC cells. Methods: The mRNA levels of KLK4 and the relationship between the KLK4 and tumor stage in patients with RCC were analyzed from the GEPIA database. Real-time PCR and Western blotting were used to measure the mRNA and protein levels of KLK4. Cell Counting Kit 8 (CCK8), colony formation, wound healing, and Transwell assays were used to examine the proliferation, invasion, and migration of RCC cells after KLK4 suppression. Finally, xenograft experiments in a mouse model helped understand in vivo effects of KLK4 knockdown. Results: Our research found that KLK4 expression was upregulated in the kidney chromophobe (KICH) specimens and cell lines. Moreover, inhibiting KLK4 growth led to a slowdown in RCC cell proliferation and colony formation. Additionally, KLK4 knockdown inhibited migration, invasion, and epithelial-mesenchymal transition (EMT) of RCC cells. AKT and ERK phosphorylation was enhanced with KLK4 silencing. In the nude mouse xenograft cancer model, KLK4 silencing also prevented the expression of Ki-67, CD105, and the growth of tumors. Conclusion: KLK4 accelerated KICH progression via ERK/AKT signaling pathway, providing a novel regulatory mechanism for KICH pathogenesis.