The exposure of the African catfish (Clarias gariepinus) to various environmental contaminants leads to physiological and histological alterations. Therefore, the study aimed to assess the impact of seasonal variations of ecological contaminants as external stressors and internal stressors via helminth infections on oxidative stress and histopathology in resident C. gariepinus at EL-Salam Canal, Egypt. Seasonal water and sediment samples were collected to assess physicochemical parameters and heavy metals. The length, weight, and sex were recorded for each fish sample. The gastrointestinal tract was dissected from the visceral cavity, and the helminths were extracted and identified using SEM photos based on their morphological characteristics. The parasitic dominance in the gastrointestinal helminths was calculated. The heavy metal concentrations, bioaccumulation (BAF), and biosedimentation (BSF) factors were considered in the muscles and intestine. Specimens of muscles and intestines were removed to determine oxidative status. In addition, pieces of skin, muscles, stomachs, and intestines were subjected to light microscopy to determine the alterations. The calcium, magnesium, and potassium levels were within safe limits. Sulfate levels consistently remained below the maximum permissible thresholds throughout the seasons. Among the heavy metals examined, the highest accumulation was found in the intestinal tissues of C. gariepinus, while muscle tissues showed lower levels. The variability in metal concentrations across water, sediment, muscles, and intestines underscores the different capacities of these environments to accumulate heavy metals. The elevated metal levels in fish tissues raise concerns about potential health risks for humans who consume contaminated fish, highlighting significant bioaccumulation within the food chain. The result indicated that Cu in the sediment samples was associated with parasite abundance. The dual stress from environmental pollutants and parasitic infections exacerbates oxidative stress and causes notable histopathological changes in the tissues of the catfish. These results highlight the intricate interplay between external and internal stressors, emphasizing the need for continuous monitoring and management of aquatic ecosystems to safeguard the health of resident fish populations. It provides insight into how these factors affect fish health.