KRAS is one of the most commonly mutated oncogenes in non-small cell lung cancer (NSCLC). Resistance to MEK inhibitor monotherapy develops through a variety of mechanisms. CDK4 was reported to have a synthetic lethal interaction with KRAS. In this study, we demonstrated the combination effects of the MEK inhibitor selumetinib and the CDK4/6 inhibitor palbociclib in RAS-driven NSCLC. In vitro, cell lines with CDKN2A mutations were insensitive to selumetinib. We used siRNA and pharmacologic inhibition of CDK4 and found that the combination of selumetinib and palbociclib synergistically inhibited RAS-driven NSCLC cases with CDKN2A mutations but not those with wild type CDKN2A. The combination treatment potentiated growth inhibition and increased the population of cells in G1 phase. Selumetinib completely inhibited p-ERK but not p-RB. The addition of palbociclib markedly inhibited p-RB and downregulated survivin expression. In vivo, the combination treatment inhibited the growth of NSCLC xenografts, which correlated with decreased levels of p-RB, downregulated survivin and decreased Ki-67 staining. These data suggest that the combination treatment of palbociclib and selumetinib is effective in preclinical models of RAS-driven NSCLC with CDKN2A mutations.