The present study aimed to investigate the role of the PI3K/Akt signaling pathway in scleral remodeling in the development of negative lens-induced myopia (LIM). The change of scleral morphology in experimental myopic guinea pigs was observed by transmission electron microscopy, Masson staining, and TUNEL assay, respectively. Meanwhile, the levels of the PI3K/AKT signaling pathway- and scleral remodeling-related molecules in scleral tissues were determined by real-time quantitative PCR (qPCR), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, immunohistochemical staining, and western blot, respectively. We found that 2-week myopic induction can elevate PIK3R3 and AKT2 levels and activate the PI3K/Akt signaling pathway, enhance the expression of E-cadherin and matrix metallopeptidase 2 (MMP2), and decrease the level of transforming growth factor-beta 1 (TGF-β1), tissue inhibitor of matrix metalloproteinase-2 (TIMP2), and collagen (COLI) in the scleral tissue of myopic guinea pigs, thereby leading to scleral remolding. However, 4-week myopic induction could inhibit the PI3K/AKT signaling pathway and induce apoptosis, accompanied by increased MMP2, E-cadherin, and decreased TGF-β1, TIMP2, and COLI. Results reveal that the disturbed PI3K/AKT signaling plays a role in scleral remodeling in the experimental myopia through orchestrating apoptosis.