Microplastics (MPs) are environmental pollutants with potential health risks. This study examined the effect of MPs on wound healing in both diabetic and non-diabetic mice. MPs exposure significantly delayed wound healing, particularly in diabetic mice, with reduced epidermal thickness and impaired collagen deposition. Mechanistically, MPs suppressed cell proliferation, angiogenesis, and increased apoptosis. Transcriptomic analysis identified dysregulation of critical wound healing pathways, especially those involved in inflammation, extracellular matrix remodeling, and lipid metabolism. Notably, the PI3K/AKT signaling pathway was inhibited. In vitro experiments using human dermal fibroblasts confirmed that MPs disrupted the PI3K/AKT pathway, reducing cell proliferation and migration. Further investigation revealed that MPs suppressed N-acetyltransferase 10 (NAT10) expression, leading to reduced ac4C-dependent stabilization of Fasn mRNA, which in turn diminished lipid synthesis and further inhibited the PI3K/AKT pathway. Our findings reveal a novel interaction between MPs and diabetes in impairing wound healing and suggest the NAT10-FASN-PI3K/AKT axis as a potential therapeutic target.