Heavy metals (HM) are widespread contaminants of water affecting aquatic organisms and aquatic ecosystems. Indian lotus, Nelumbo nucifera (Gaertn.), is a beneficial medicinal plant that exhibits several pharmacological properties. It is hypothesized that incorporation of Indian lotus leaf (ILL) powder may be able to alleviate toxic effects exerted by a mixture of lead (Pb), cadmium (Cd), mercury (Hg), and zinc (Zn) in Nile tilapia, Oreochromis niloticus (L.). A total of two hundred and forty fish were randomly allocated into eight groups in triplicate, in a bifactorial design (4 ILL levels × 2 HM exposures). The fish in the first four groups were fed on a basal diet (39.9% crude protein) that was enriched with 0.0, 0.1, 0.2, and 0.4% ILL (in G1–G4, respectively), with no HM exposure. In the remaining four groups, fish were fed with the same diets and, in addition, were exposed to 1/20 of the 96 h-LC50 of Pb, Cd, Hg, and Zn mixture (in G5–G8, respectively), for 45 days. The HM exposure significantly elevated the levels of serum alanine and aspartate aminotransferases, creatinine, urea, malondialdehyde, and activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX). The expression level of hepatic metallothionein (MT) was up-regulated as well as high residual levels of HM in fish musculature were recorded in the HM-exposed fish. Two-way ANOVA revealed that all the studied variables were significantly affected by the ILL supplementation, HM exposure, and their interaction. Moreover, levels of MDA, CAT, SOD, and MT showed significant positive correlations with HM concentrations. Moreover, necrosis and degeneration of hepatopancreatic cells with congestion, hyperplasia, and fusion of gills lamellae were observed in HM-exposed fish. Interestingly, ILL supplementation, especially in the fish fed with 0.2 and 0.4% ILL, was observed to reduce the HM concentration in the fish body, resulting in the reduction of its toxic effects on the biochemical and antioxidant activities. These results demonstrated that dietary ILL supplementation could protect Nile tilapia against the toxic effects of HM, and therefore, may serve as a beneficial feed additive for application in the aquaculture industry.