The development of new fungicides is vital for safeguarding crops and ensuring sustainable agriculture. Building on our previous finding that 4-(3,4-dichloroisothiazole)-7-hydroxy coumarins can be used as fungicidal leads, 44 novel coumarin ester derivatives were designed and synthesized to evaluate whether esterification could enhance their fungicidal activity. In vitro fungicidal bioassays indicated that compound2aidisplayed good activity againstAlternaria solani,Botrytis cinereal,Cercospora arachidicola,Physalospora piricolaandSclerotinia sclerotiorum, with an EC50value ranging from 2.90 to 5.56 μg/mL, comparable to the lead compound1a, with its EC50value ranging from 1.92 to 9.37 μg/mL. In vivo bioassays demonstrated that compounds1a,2arand2bgshowed comparable, excellent efficacy againstPseudoperonospora cubensisat a dose of 25 µg/mL. Our research shows that the esterification of 4-(3,4-dichloroisothiazole) 7-hydroxycoumarins results in a fungicidal activity equivalent to that of its lead compounds. Furthermore, our density functional theory (DFT) calculations and 3D-QSAR modeling provide a rational explanation of the structure–activity relationship and offer valuable insights to guide further molecular design.