High myopia is a risk factor for primary open angle glaucoma (POAG). The pathological mechanism of high myopia induced POAG occurrence is not fully understood. In this study, we successfully established the guinea pig model of ocular hypertension with high myopia, and demonstrated the susceptibility of high myopia for the occurrence of microbead-induced glaucoma compared with non-myopia group and the effect of YAP/TGF-β signaling pathway in TM pathogenesis induced by high myopia. Moreover, we performed stretching treatment on primary trabecular meshwork (TM) cells to simulate the mechanical environment of high myopia. It was found that stretching treatment disrupted the cytoskeleton, decreased phagocytic function, enhanced ECM remodeling, and promoted cell apoptosis. The experiments of mechanics-induced human TM cell lines appeared the similar trend. Mechanically, the differential expressed genes of TM cells caused by stretch treatment enriched YAP/TGF-β signaling pathway. To inhibit YAP/TGF-β signaling pathway effectively reversed mechanics-induced TM damage. Together, this study enriches mechanistic insights of high myopia induced POAG susceptibility and provides a potential target for the prevention of POAG with high myopia.