Objective: To evaluate the association between oxidative stress markers and pro-inflammatory cytokines in patients with chronic rhinosinusitis (CRS) with and without nasal polyps. Methodology: This comparative cross-sectional study was conducted at a tertiary care hospital in Lahore, Pakistan, from January 2023 to December 2024. A total of 120 patients diagnosed with CRS were enrolled and divided into two equal groups: CRS without nasal polyps (CRSsNP, n=60) and CRS with nasal polyps (CRSwNP, n=60). Diagnosis was confirmed clinically and by nasal endoscopy and/or computed tomography. Serum levels of malondialdehyde (MDA), total antioxidant capacity (TAC), superoxide dismutase (SOD), catalase, and nitric oxide were measured to assess oxidative stress. Pro-inflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and high-sensitivity C-reactive protein (hs-CRP) were quantified using ELISA. Data were analyzed using SPSS, and a p-value <0.05 was considered statistically significant. Results: CRSwNP patients demonstrated significantly higher levels of MDA, nitric oxide, IL-6, TNF-α, IL-1β, and hs-CRP compared to CRSsNP patients (p<0.001), while antioxidant parameters (TAC, SOD, catalase) were significantly reduced (p<0.001). CT severity scores positively correlated with oxidative and inflammatory markers and inversely correlated with antioxidant levels (p<0.001). Multivariate analysis identified elevated MDA and IL-6 as independent predictors of nasal polyp formation. Conclusion: CRSwNP is characterized by heightened oxidative stress and amplified inflammatory cytokine activity. The significant association between oxidative imbalance and inflammatory mediators suggests their potential role as biomarkers for disease severity and polyp formation in chronic rhinosinusitis.