One of the challenges facing aquaculture is finding a high-value, sustainable, and low-cost alternative feedstuff. Duckweed, a small aquatic plant, has a high-quality protein value. This study was conducted to evaluate the impact of aquaponically produced duckweed L. minor as a substitute feedstuff and its effect of different levels (0, 10, 20, and 30%) on water quality, growth indices, digestive activities, and profitability of the Nile tilapia Oreochromis niloticus fingerlings (15.27± 0.19g) using aquaponics system for 8 weeks. With a completely randomized design, fish were stocked (6kg/ m3) in 12 experimental aquaponic units (250L). Results showed that duckweed inclusion had a significant impact on water quality measures (P< 0.05), leading to a drop in nitrogen and phosphorus levels in fish tanks. Duckweed improved growth indexes, digestive enzyme activities, and profitability (P< 0.05). At a substitution rate of 20% of duckweed in the diet, the feeding impact was at its peak, resulting in a weight gain rate of 63.2g in 56 days, which was 32.7% greater than the control group (P< 0.05). Compared to the control group, the fish showed significantly higher body weight, specific growth rate, feed conversion ratio, condition factor, and hepatosomatic index (P< 0.05). Duckweed stimulated the digestive system's amylase, protease, and lipase activity (P< 0.05). Based on the findings, it can be reported that, the Nile tilapia fingerlings reared in an aquaponics system can include duckweed at a rate of 20% in diet to show better growth indices and profitability.