Polybrominated diphenyl ethers (PBDEs) are chemical compounds that have been extensively utilized for several decades as flame retardant additives in combustible materials, including construction and textile products, exhibiting detrimental effects on aquatic organisms. This study aimed to quantify the bioaccumulation of PBDEs in the tissues of Tilapia zilli from Lekki Lagoon. Physicochemical parameters at selected sites within Lekki Lagoon were assessed using a handheld Horiba (μ-50) device; all observed parameters were within the permissible limits set by the Federal Environmental Protection Agency (FEPA). PBDE concentrations in the tissues were analyzed using gas chromatography-mass spectrometry (GC-MS), while levels of oxidative stress enzymes were determined via atomic absorption spectrophotometry (AAS). Seven PBDE congeners were identified in the tissues of uninfected T. zilli, whereas two PBDE congeners were detected in the tissues of infected specimens. The average concentration of BDE-28 (244′-tribromodiphenyl ether) in the tissue of uninfected fish was statistically higher (p < 0.001) compared to infected fish. Generally, the total PBDE level was significantly higher in uninfected compared to infected fish tissues. BDE-209 was not detected in both groups of test organisms. Malonaldehyde level in uninfected T. zilli was higher at 7.4 μmol/mL compared with infected T. zilli at 4 μmol/mL. Catalase level was significantly (p < 0.001) higher in uninfected tissues. Cholesterol, high-density lipid, and low-density lipid levels were significantly higher p < 0.001 in uninfected fish tissues. Findings from this study provide evidence that PBDE contamination in Lekki Lagoon induces oxidative damage in native fish species.