Crosstalk between salicylic acid (SA) and jasmonic acid (JA) signaling is well-studied but not during leaf senescence. We found that the senescence-specific WRKY53 transcription factor interacts with the JA-inducible protein EPITHIOSPECIFYING SENESCENCE REGULATOR (ESR/ESP). The expression of these genes is antagonistically regulated in response to JA and SA, respectively, and each negatively influences the other. Leaf senescence is accelerated in ESR knockout plants (ESR-KO) but retarded in ESR overexpressors (ESR-OE), with the reverse true for WRKY53. ESR-OE showed higher resistance than ESR-KO to bacterial and fungal pathogens. However, pathogen resistance was not altered in WRKY53 overexpressors or knockouts (W53-KO), suggesting that ESR has a greater impact on WRKY53 function in senescence than WRKY53 on ESR function in pathogen resistance. ESR inhibits WRKY53 DNA binding in vitro, and their interaction is localized to the nucleus in vivo; however, ESR is exclusively in the cytoplasm in W53-KO cells, indicating that ESR is brought to the nucleus by the interaction. Therefore, ESR has dual functions: as cytoplasmic epithiospecifier and as negative regulator of WRKY53 in the nucleus. These results suggest that WRKY53 and ESR mediate negative crosstalk between pathogen resistance and senescence, which is most likely governed by the JA and SA equilibrium.