Cellular tumor antigen p53 (p53) functions to maintain genomic stability and regulate cell apoptosis, while G protein?coupled receptor class C group 5 member?A (GPCR5A) is a lung cancer suppressor gene whose expression is induced by retinoids. The present in?vitro study assessed the effects of p53 on the regulation of GPRC5A expression and on non?small cell lung cancer (NSCLC) cells. Human NSCLC H1299 (p53?null) and A549 (wild?type p53) cell lines were subjected to p53 cDNA and small interfering (si)RNA transfection, respectively. GPRC5A expression was analyzed by reverse transcription?quantitative polymerase chain reaction and western blotting, and cell behavior was analyzed using cell viability and apoptosis assays. The results of the present study demonstrated that knockdown of GPRC5A expression markedly upregulated tumor cell viability and reduced tumor cell apoptosis, while p53 overexpression in H1299 cells significantly increased the expression level of GPRC5A. p53 overexpression and GPRC5A induction markedly inhibited tumor cell viability and induced apoptosis, while knockdown of p53 resulted in a decrease in GPRC5A expression, inhibited tumor cell apoptosis and increased tumor cell viability. In serum?free culture conditions, GPRC5A expression was decreased in the two cell lines; this decrease was less marked in p53 cDNA?transfected H1299 cells and more marked in p53 siRNA?transfected A549 cells. The results of the present study indicated that p53 antitumor activity may be mediated by GPRC5A in NSCLC cells.