Objective: The study aims to assess the overall safety of cultured tilapias in Jeddah City, Saudi Arabia by assessing the impact of infection and anthropogenic pollution on farmed tilapias based on fish sex, body weight, length, and heavy metals contamination. Materials and methods: A total of 111 fish were collected from an aquaculture farm in Hada Al-Sham, Jeddah, Saudi Arabia. Physicochemical parameters of water from the culture system were evaluated. Both ecto- and endoparasites were checked. Haematological, biochemical and histopathological investigations were evaluated. In addition, heavy metals, namely, cadmium (Cd), chromium (Cr), copper (Cu), nickel (Ni), lead (Pb), and zinc (Zn) were evaluated in different fish tissues and water samples from the aquaculture system. Results: The study revealed stressed aquaculture system. Tilapias were infested by both ectoparasites including Trichodina, Icthyophthirius multifiliis, Dactylogrus, and Cichlidogyrus, and endoparasites as Icthyophonus hoferi, the nematode Capillaria and coccidian protozoa. The study showed that male tilapias had greater infestation rates than females and longer and heavier male fish tended to be more susceptible to Dactylogyrus infection. Infected fish showed altered biochemical markers with subsequent increases in inflammatory and oxidative stress markers. The post-mortem lesion in the skin, gill lamellae, intestine, spleen, and liver showed significant pathological remarks. All investigated fish tissues revealed higher rates of heavy metals bioaccumulation compared to the surrounding waters. On the other hand, infected Nile tilapia tissues showed higher rate of metals accumulation compared to non-infected ones. Metals accumulated at a higher rate in the liver followed by kidney, intestine, gills, and muscles, respectively. Conclusions: This study is recognized as the first to address the food safety of farmed tilapias in Jeddah, Saudi Arabia. The results emphasized a significant relation between parasites and heavy metal in disrupting fish defense systems and harming fish’s physiological homeostasis and the histological state of tissues. The parasitized and polluted farmed fish pose health risk to humans due to possible zoonosis from parasitic infections and its subsequent bacterial infections with long-term exposure to toxic chemicals. Addressing the need for a combination of improved aquaculture practices, and stringent regulatory oversight.