High cadmium (Cd) concentrations pose a threat to aquatic life globally. This study examined the efficiency of adding purslane (Portulaca oleracea L.) leaf powder (PLP) to Oreochromis niloticus diets on Cd’s negative effects. PLP was analyzed using high-performance liquid chromatography, and its main constituents were gallic acid, chlorogenic acid, and pyrocatechol. Nile tilapia (180 fish, 34.5 ± 0.5 g) were divided into four groups in triplicate. A basal diet was given to the control group. The PLP group received a basal diet containing 10 g PLP/kg diet. The Cd group was exposed to 50 µg/L water. The Cd + PLP group was exposed to Cd and fed diets containing PLP. Results showed that PLP significantly rescued Cd-induced effects. PLP improved fish survival, feed conversion ratio, and growth retardation caused by Cd. PLP also restored decreased activities of lipase, trypsin, and amylase in the intestine. Furthermore, PLP corrected disturbances in leptin and growth hormone levels induced by Cd. PLP mitigated pathological alterations, replenished antioxidants (SOD, CAT, and GSH), and reduced lipid peroxidation in the intestinal tissues. PLP supplementation depleted significant Cd accumulation in the intestine and muscles. Additionally, PLP corrected altered expressions of tight junction proteins (zo-1, zo-2, and claudin-4) and nutrient transporters (glut-1, slc15a2, slc26a6, and slc4a4) in Cd-exposed fish. Conclusively, PLP shows promise as a dietary supplement to mitigate Cd’s harmful impacts on fish growth. Its antioxidant activity and regulation of intestinal tight junction proteins and nutrient transporters contribute to its effectiveness. PLP supplementation holds the potential for reducing the detrimental effects of Cd in aquaculture.