Advanced glycation end products (AGEs) are the products formed through a non-enzymatic reaction of reducing sugars with proteins or lipids. There is a potential for toxicity in the case of AGEs produced through glycation with dicarbonyl compounds including methylglyoxal, glyoxal, and 3-deoxyglucosone. The AGEs bind the receptor for advanced glycation end products (RAGE) and stimulate the mitogen-activated protein (MAP) kinase signaling pathway that can increase the production of matrix metalloproteinases (MMPs). In addition, AGE-induced protein kinase B (Akt) signaling can promote cancer cell proliferation and contribute to many diseases such as kidney cancer. In light of the lack of extensive study of the relationship between methylglyoxal-induced AGEs (AGE4) and renal cancer, we studied the proliferous and anti-apoptotic effects of AGE4 on renal cell carcinoma (RCC) in this study. AGE4 treatment was involved in the proliferation and migration of RCC cells in vitro by upregulating proliferating cell nuclear antigen (PCNA) and MMPs while suppressing apoptotic markers such as Bax and caspase 3. Moreover, Akt and extracellular-signal-regulated kinase (ERK) were phosphorylated in RCC cells with AGE4 treatment. As a result, this study demonstrated that AGE4-RAGE axis can promote the growth ability of RCC by inducing PCNA, MMPs, and inhibiting apoptosis in RCC via the Akt and ERK signaling pathways.