The phytohormone salicylic acid (SA) plays a pivotal role in plant defense against biotrophic and hemibiotrophic pathogens. NPR1 and EDS1 function as two central hubs in plant local and systemic immunity. However, it is unclear how NPR1 orchestrates gene regulation and whether EDS1 directly participates in transcriptional reprogramming. Here, we show that NPR1 and EDS1 synergistically activate pathogenesis-related (PR) genes and plant defenses by forming a protein complex and recruiting Mediator. We discover that EDS1 functions as an autonomous transcriptional coactivator with intrinsic transactivation domains and physically interacts with the CDK8 subunit of Mediator. Upon SA induction, EDS1 is directly recruited by NPR1 onto the PR1 promoter via physical NPR1-EDS1 interactions, thereby potentiating PR1 activation. We further demonstrate that EDS1 stabilizes NPR1 protein and NPR1 transcriptionally up-regulates EDS1. Our results reveal an elegant interplay of key coactivators with Mediator and elucidate important molecular mechanisms for activating transcription during immune responses.