The RNA-binding protein Rbm38 is a target of p63 tumor suppressor and can in-turn repress p63 expression via mRNA stability. Thus, Rbm38 and p63 form a negative feedback loop. To investigate the biological significance of the Rbm38-p63 loop in vivo, a cohort of WT, Rbm38-/-, TAp63+/-, and Rbm38-/-;TAp63+/- mice were generated and monitored throughout their lifespan. While mice deficient in Rbm38 or TAp63 alone died mostly from spontaneous tumors, compound Rbm38-/-;TAp63+/- mice had an extended lifespan along with reduced tumor incidence. We also found that loss-of-Rbm38 markedly decreased the percentage of liver steatosis in TAp63+/- mice. Moreover, we found that Rbm38 deficiency extends the lifespan of tumor-free TAp63+/- mice along with reduced expression of senescence-associated biomarkers. Consistent with this, Rbm38-/-;TAp63+/- MEFs were resistant, whereas Rbm38-/- or TAp63+/- MEFs were prone, to cellular senescence. Importantly, we showed that the levels of inflammatory cytokines (IL17D and Tnfsf15) were significantly reduced by Rbm38 deficiency in senescence-resistant Rbm38-/-;TAp63+/- mouse livers and MEFs. Together, our data suggest that Rbm38 and p63 function as intergenic suppressors in aging and tumorigenesis and that the Rbm38-p63 loop may be explored for enhancing longevity and cancer management.