Regulator of G protein signaling 20 (RGS20) has been shown to be highly expressed in various types of cancer. The present study aimed to investigate the effects of RGS20 in patients with renal cell carcinoma (RCC) and in RCC cells. Bioinformatics analysis was performed to analyze the role of RGS20 in RCC. Quantitative PCR and western blotting were used to determine the mRNA and protein expression levels of RGS20 in cells, respectively. After RGS20 inhibition, the proliferation, apoptosis, migration and invasiveness of A-498 cells were tested using MTT assay, EdU assay, propidium iodide staining, Annexin V-FITC/PI kit, wound healing assay and Transwell assay. High RGS20 expression was closely associated with the progression and immune infiltration of RCC, and may be considered as an independent indicator of poor prognosis in RCC. After knocking down RGS20, the proliferation, migration and invasiveness of cells were impaired, the cell cycle was arrested at the G/G phase, and the level of apoptosis was increased. In addition, the mRNA expression levels of securin, CDC20 and cyclin B1 were decreased in RGS20-knockdown cells. RGS20 expression was significantly associated with the infiltration level of activated CD4 T cells, type 1 T helper cells and activated dendritic cells. In summary, RGS20 expression was associated with RCC progression and poor prognosis; thus, it may be used to estimate the prognosis of RCC and may serve as a new potential treatment strategy for RCC.