This study investigated the efficacy of incorporating purslane (Portulaca oleracea L.) leaf powder (PUP) into the diets of Oreochromis niloticus to enhance immune function, improve disease resistance against cadmium (Cd) exposure, and explore the potential underlying mechanisms. In this study, 180 Nile tilapia fingerlings were allocated into four groups in triplicate. The control group received a basal diet, while the PUP group was fed a basal diet supplemented with 10 g of PUP/Kg. The Cd group was exposed to 50 µg/L of Cd in water, and the Cd + PUP group was exposed to Cd and fed a PUP-supplemented diet. Results revealed that PUP significantly alleviated Cd-induced anemia and heteropenia. PUP improved innate immune function including serum contents of complement 3 and nitric oxide as well as lysozyme activity. Besides, PUP reduced spleen damage, restored serum antioxidants (GSH, CAT, SOD, GPx, GST, and GSR), and decreased lipid peroxidation. Moreover, PUP corrected altered expressions of oxidative stress (sod-1, sod-2, cat, and gpx)– and autophagy (nf-κb, hsp70, mTOR, jnk, akt, beclin-1, and lc3)–related genes in Cd-exposed fish. Furthermore, PUP decreased fish mortality during the 14-day challenge to Aeromonas hydrophila infection. In conclusion, our study revealed that PUP addition to Nile tilapia diets significantly boosted the immune function and disease resistance in fish reared under Cd stress possibly via modulating oxidative stress and autophagy pathways. Thus, PUP dietary supplementation could serve as a beneficial immunostimulant aqua additive.