Deltamethrin (DLM) is a member of pyrethroid pesticide widely applied for agriculture and aquaculture, and its residue in the environment seriously threatens the bio-safety. The cerebrum might be vulnerable to pesticide-triggered oxidative stress. However, there is no specific antidote for treating DLM-triggered cerebral injury. Selenium (Se) is an essential trace element functionally forming selenoprotein glutathione peroxidase (GPX) in antioxidant defense. Se yeast (SY) is a common and effective organic form of Se supplement with high selenomethionine content. Accordingly, this study focused on investigating the therapeutic potential of SY on DLM-induced cerebral injury in quails after chronically exposing to DLM and exploring the underlying mechanisms. Quails were treated with/without SY (0.4 mg kg⁻¹ SY added in standard diet) in the presence/absence of DLM (45 mg kg⁻¹ body weight intragastrically) for 12 weeks. The results showed SY supplementation ameliorated DLM-induced cerebral toxicity. Concretely, SY elevated the content of Se and increased GPX4 level in DLM-treated quail cerebrum. Furthermore, SY enhanced antioxidant defense system by upregulating nuclear factor-erythroid-2-related factor 2 (Nrf2) associated members. Inversely, SY diminished the changes of apoptosis- and inflammation-associated proteins and genes including toll-like receptor 4 (TLR4). Collectively, our results suggest that dietary SY protects against DLM-induced cerebral toxicity in quails via positively regulating the GPX4/TLR4 signaling pathway. GPX4 may be a potential therapeutic target for insecticide-induced biotoxicity.