The purpose of the study was to ascertain the preventative value of dietary supplements with fruits of the prickly pear on the haemato-biochemical and immunological responses of O. niloticus exposed to subacute waterborne cadmium toxicity. Four diets supplemented with different proportions of fruits of 0% (control, OLFE-0% group), 0.5% (OLFE-0.5% group), 1% (OLFE-1% group), and 2% (OLFE-2% group) were administered to tilapia fingerlings for sixty days (pre-cadmium). After the feeding session, the tilapia treatments were subjected to waterborne cadmium toxicity for four days (post-cadmium). Blood samples were captured pre- and post-cadmium exposure to assess the haemato-biochemical and immunological alternations. According to the current findings, nutritional meals fortified with OLFE can enhance tilapia fish's growth performance and digestive enzymes. Nile tilapia fed on OLFE-fortified diets showed a significant reduction in cortisol, alanine transaminase (ALAT), aspartate transaminase (ASAT), glucose, protein, and malondialdehyde (MDA) compared to the control with a basal diet without OLFE (P < 0.05). Additionally, it significantly improves the activities of complement C3, lysozyme, catalase (CAT), total immunoglobulin, superoxide dismutase (SOD), and glutathione peroxidase (GPX). Significant increases in cortisol, leukocytes, glucose, CAT, ALAT, GPX, ASAT, and SOD were observed following exposure to waterborne cadmium. At the same time, there were decreases in erythrocytes, blood indices, hemoglobin, complement C3, packed cell volume, lysozyme, total immunoglobulin, and malondialdehyde (MDA) values. In brief, these findings suggest that supplementing prickly pear fruits to tilapia diets, especially at a level of 2%, can enhance immunological and antioxidant properties and effectively mitigate the harmful effects of Cd exposure in food safety and aquaculture.