We studied the oxidative stress and osmoregulatory damage as well as the accumulation of lead in Mozambique Tilapia Oreochromis mossambicus exposed to different sublethal concentrations-low, medium, and high (0.5, 2.5, and 5.0 mg/L)-of waterborne lead for 14 d in a semistatic condition. The accumulated levels of Na+, K+-ATPase, glutathione (GSH), and thiobarbituric acid reactive substances (TBARS) were determined from samples of gill, liver, intestine, brain, kidney, and muscle tissues. At the end of the experiment, the GSH levels of most tissues were higher in the treated group than in the control group (especially in the liver and kidney) but lower in the intestine. The levels of TBARS in the gill and brain tissues of the fish exposed to high lead doses were significantly higher than those of fish in the control group. Na+, K+-ATPase activity seemed to be significantly inhibited in the gill, intestine, and brain tissues across all treatment groups. At the end of the study, the total amount of lead that had accumulated within the various tissues ranked as follows: intestines > kidney > brain > gill > liver > muscle. Our findings suggest that sublethal concentrations of lead can disrupt the health of Mozambique Tilapia and cause oxidative stress and osmoregulatory damage.