MAPKs have been intensively studied in yeast and mammals. However, the functions of MAPKs in plants remain largely unknown. In this study, we show silencing a MAPK, NaMPK4, in a wild tobacco species, N. attenuata, enhances plant fitness and elevates defense levels against herbivores, but compromises resistance to pathogens and drought stress. NaMPK4 regulates certain (but not all) ABA-, salt-, and MeJA-induced responses: it is required for the inhibitory effect of these compounds in germination, but is not involved these compounds’ suppression of root elongation or in the regulation of gene expression after drought or MeJA treatment. Importantly, NaMPK4 acts downstream of ABA-induced H2O2 to promote stomatal closure and is also very likely to be required for stoma-mediated pathogen defense. NaMPK4 is also specifically activated by FACs and negatively mediates a JA-independent defense pathway against insect herbivore, M. sexta. These data highlight the important function of NaMPK4 in mediating various ecologically important traits in N. attenuata. Large scale transcriptome analysis and phosphorylation target identification will shed light on the molecular basis of NaMPK4’s function in plant development and resistance to biotic and abiotic stresses. Studying the performance of irNaMPK4 plants in N. attenuata’s natural habitat, where these plants are challenged with a full spectrum of biotic and abiotic factors, will provide further insight into the ecological and evolutionary significance of NaMPK4. Furthermore, we propose that homologues of MPK4 in agriculturally important seed crops may be potential targets for genetically modification to increase seed yield and resistance to herbivores and pathogens.