Introduction: Smoking is a modifiable risk factor implicated in numerous chronic diseases, including renal dysfunction. Understanding its impact on renal function among middle-aged adults is essential for preventive health strategies. Objective: This study evaluates the relationship between smoking and renal function decline in middle-aged adults, with emphasis on the differences between smokers and non-smokers. Methods: A cross-sectional study was conducted among 400 participants aged 40–65, divided into smokers (n=200) and non-smokers (n=200). Renal function was assessed using serum creatinine levels, estimated glomerular filtration rate (eGFR), and albumin-to-creatinine ratio (ACR). Statistical significance was determined using Student’s t-test and multivariate regression analysis, adjusted for confounding factors. Results: Smokers demonstrated significantly lower eGFR values (mean ± SD: 75.2 ± 10.6 vs. 89.1 ± 12.3, p<0.001) and higher ACR (mean ± SD: 34.5 ± 8.9 vs. 18.7 ± 5.6, p<0.001) compared to non-smokers. Regression analysis confirmed smoking as an independent predictor of renal function decline (β=-0.27, p<0.01). Discussion & Conclusion: This study highlights significant renal impairment among smokers, emphasizing the critical need for targeted smoking cessation interventions. Novel findings on middle-aged populations underscore the study’s contribution to current research gaps and call for longitudinal studies to further explore causality.