Particulate matter 2.5 (PM2.5) causes skin aging, inflammation, and impaired skin homeostasis. Hyperoside, a flavanol glycoside, has been proposed to reduce the risk of diseases caused by oxidative stress. This study evaluated the cytoprotective potential of hyperoside against PM2.5-induced skin cell damage. Cultured human HaCaT keratinocytes were pretreated with hyperoside and treated with PM2.5. Initially, the cytoprotective and antioxidant ability of hyperoside against PM2.5 was evaluated. Western blotting was further employed to investigate endoplasmic reticulum (ER) stress and cellular senescence and for evaluation of cell cycle regulation-related proteins. Hyperoside inhibited PM2.5-mediated ER stress as well as mitochondrial damage. Colony formation assessment confirmed that PM2.5-impaired cell proliferation was restored by hyperoside. Moreover, hyperoside reduced the activation of PM2.5-induced ER stress-related proteins, such as protein kinase R-like ER kinase, cleaved activating transcription factor 6, and inositol-requiring enzyme 1. Hyperoside promoted cell cycle progression in the G0/G1 phase by upregulating the PM2.5-impaired cell cycle regulatory proteins. Hyperoside significantly reduced the expression of PM2.5-induced senescence-associated β-galactosidase and matrix metalloproteinases (MMPs), such as MMP-1 and MMP-9. Overall, hyperoside ameliorated PM2.5-impaired cell proliferation, ER stress, and cellular senescence, offering potential therapeutic implications for mitigating the adverse effects of environmental pollutants on skin health.