Background <p>Nanoplastics (NPs) have emerged as environmental contaminants posing potential risks to human health. Recently, skeletal muscle has been recognized as a target tissue affected by NP exposure, where NPs trigger premature cellular senescence.</p> Objective <p>This study aimed to determine whether senescence induced by polystyrene NPs (PS-NPs) in pre-differentiated C2C12 myoblasts is regulated by nuclear factor erythroid 2-related factor 2 (Nrf2), a redox-sensitive transcription factor.</p> Methods <p>After confirming that PS-NPs induce cellular senescence in C2C12 myoblasts, we examined whether sulforaphane, an Nrf2 activator, attenuates this process by enhancing antioxidant defense and maintaining mitochondrial homeostasis. Additionally, we investigated the effects of <i>Nrf2</i> knockdown on PS-NP-mediated cellular senescence.</p> Results <p>PS-NP exposure downregulated and dephosphorylated Nrf2, whereas sulforaphane treatment restored its expression and phosphorylation, concomitant with the upregulation of heme oxygenase-1 activity. Sulforaphane significantly attenuated PS-NP-induced premature cellular senescence, as evidenced by reduced β-galactosidase activity and senescence-associated marker levels and suppressed senescence-associated secretory phenotypes. Moreover, sulforaphane preserved mitochondrial integrity and decreased both intracellular and mitochondrial reactive oxygen species levels, indicating that its anti-senescence effects were mediated <i>via</i> activation of the Nrf2/heme oxygenase-1 pathway. Conversely, <i>Nrf2</i> knockdown markedly exacerbated PS-NP-induced cellular senescence.</p> Conclusions <p>Overall, these findings suggest that sulforaphane-mediated activation of Nrf2 mitigates PS-NP-induced premature myoblast senescence through redox regulation, underscoring the essential role of antioxidant defense pathways in protecting skeletal muscle cells from nanoplastic-induced cellular senescence.</p>