Exposure to polycyclic aromatic hydrocarbons (PAHs) and tobacco smoke is widespread and linked to various adverse health outcomes. Their potential to disturb the neurological system has raised much concern, particularly among older adults. Thus, we conducted a case-control study to assess the associations between co-exposure to PAHs and nicotine, and the risk of cognitive impairment and oxidative stress in older adults. A total of 384 adults aged 60 years and older were recruited from 2017 to 2018 in Shenzhen, China. Morning spot urine samples were collected for the analysis of 6 mono-hydroxylated PAHs, 8 nicotine metabolites, and a typical biomarker for oxidative stress, 8-hydroxy-2'-deoxyguanosine (8-OHdG). The Mini-Mental State Examination was used to assess the cognitive function of participants. Quantile-based g-computation (QGC), weighted quantile sum regression, and Bayesian kernel machine regression were used to analyze the associations between the exposure mixture and outcomes. QGC showed co-exposure to PAHs and nicotine were positively associated with cognitive impairment risk (OR: 1.66, 95% CI: 1.36-2.03, P <
0.001) and 8-OHdG (β:11.19, 95% CI: 3.90-18.48, P <
0.001). The primary contributors to cognitive impairment risk were (S)-nicotine-N-β-glucuronide (NicGluc), cotinine N-β-D-glucuronide (CotGluc) and (S)-cotinine N-oxide (CNO) and Cotinine (Cot), with no-linear dose-response relationships. However, 8-OHdG did not mediate the association between PAHs, nicotine and cognitive impairment risk.