Background <p>Oxidative stress and lipid metabolism disruptions drive COVID-19 severity, but data from African populations, particularly Nigeria, are limited. This study explored malondialdehyde (MDA), 8-iso-prostaglandin F2α (8-iso-PGF2α), and lipid profile changes in COVID-19 patients in South-Western Nigeria, emphasizing co-infections.</p> Methods <p>This cross-sectional study included 60 COVID-19 patients, with and without comorbidities, and 50 healthy controls at three Lagos isolation centers from July to December 2021. Disease severity (mild, moderate, severe) was assessed using clinical, oxygen saturation, and radiologic criteria. Serum MDA and lipid profiles were measured by spectrophotometry, and 8-iso-PGF2α by enzyme-linked immunosorbent assay. ANOVA with Tukey post-hoc tests analyzed normally distributed variables, and Kruskal–Wallis tests evaluated skewed variables. Age-adjusted comparisons used ANCOVA, with log-transformation for non-normal data. Spearman’s correlation assessed relationships between oxidative stress and lipid parameters, with Bonferroni correction for multiple comparisons.</p> Results <p>COVID-19 patients showed elevated MDA, 8-iso-PGF2α, triglycerides, and TG/HDL-C ratios (<i>p</i> ≤ 0.001), and reduced total cholesterol, LDL-C, and HDL-C (<i>p</i> ≤ 0.001) compared to controls. Oxidative stress markers correlated with lipid parameters, suggesting cardiovascular risk. Severe cases and malaria co-infected patients had more pronounced changes, though small subgroup sizes limited findings.</p> Conclusion <p>COVID-19 in Nigerian patients shows elevated MDA, 8-iso-PGF₂α, and dyslipidaemia (higher triglycerides, TG/HDL-C ratio, lower HDL-cholesterol), worsened by severity and malaria co-infection. These suggest biomarkers for risk stratification and therapy. The cross-sectional design limits causality, requiring larger, prospective studies for metabolic monitoring in co-endemic settings.</p> Clinical trial number <p>Not applicable.</p>