Abstract: Herbivore effectors play central roles in plant–insect interactions; yet, their molecular targets and modes of action remain poorly defined. Here, we performed data-independent acquisition proteomic profiling of oral secretions from cotton bollworm (Helicoverpa armigera) larvae fed on an artificial diet and four cotton cultivars. A total of 212 proteins were identified, including 39 differentially expressed proteins and 13 candidate effectors. Based on secretion characteristics and evolutionary features, six venom protein-related candidates were selected for functional validation. Transgenic cotton plants overexpressing these genes were generated, and feeding assays demonstrated that three independent 35S:PESD3 lines and three 35S:HYPB1 lines significantly enhanced bollworm performance relative to wild-type cotton. Further analyses showed that HYPB1 and PESD3 can be secreted into cotton tissues through mechanical wounds. Among these candidates, HYPB1 showed typical structural and evolutionary characteristics of venom-related proteins. Multiple complementary protein–protein interaction assays demonstrated that HYPB1 physically interacts with the cotton dirigent protein GhDIR15. Silencing of GhDIR15 via virus-induced gene silencing reduced cotton resistance to H. armigera and was accompanied by decreased lignin accumulation and reduced phenolic metabolite levels, indicating suppression of the cell wall-associated defense pathway. Together, these results identify HYPB1 as a previously uncharacterized effector that promotes bollworm feeding by targeting GhDIR15 and suppressing lignin biosynthesis, thereby further compromising cell wall-mediated defense. Although PESD3 also promoted bollworm performance in transgenic cotton, its underlying mechanism requires further investigation. This work provides mechanistic insight into how H. armigera manipulates host secondary metabolism to attenuate plant defense.