The object of this study was to investigate the molecular mechanisms mediating TNFalpha-induced apoptosis and autophagy in L929 cells. Herein, we found that the treatment of L929 cells with TNFalpha caused a time-dependent increase in p53 activity. The inhibition of p53 activation reduced TNFalpha-induced apoptosis and autophagy that were accompanied by the decrease in the levels of AIF, Beclin1 and LC3. Subsequently, TNFalpha activated ERK, JNK and p38 in apoptosis and autophagy, in which ERK/JNK played a promoting role whereas p38 played an inhibiting one. In addition, TNFalpha-induced p53 activation was reduced by ERK or JNK inhibition, but it was not affected by p38 inhibition. Further data showed that the inhibition of autophagy reduced TNFalpha-induced apoptosis in L929 cells. In conclusion, these results demonstrate that TNFalpha-induced MAPKs mediate p53 activation in apoptotic and autophagic cell death, as well as autophagy may amplify apoptosis when associated with a death signaling pathway.