Earlier research has mostly focused on the impacts of stocking density on fish growth, yield, and survival rate; however, knowledge of the effects of stocking larger-sized fish, particularly Nile Tilapia, is lacking. This type of research is critically important for increasing food security, achieving sustainable goals, and facing the challenges of climate change in the near future. Therefore, we investigated the effects of initial stocking body sizes of Nile Tilapia (Oreochromis niloticus) on water quality, growth performance, and economic yield in tropical riverine cages for 120 days in two culture cycles. Nile Tilapia of three different body sizes (34.06 ± 0.22 g, 10.98 ± 0.09 g, and 5.47 ± 0.04 for the first cycle and 33.85 ± 0.01 g, 11.07 ± 0.05 g, and 5.38 ± 0.06 g for the second cycle, indicated as T1, T2, and T3) were stocked in the culture treatments where unique stocking density and feed rations were maintained. The results revealed that water quality parameters did not differ significantly (p > 0.5) and were within a suitable range for Nile Tilapia culture. Treatments with larger-sized fish demonstrated a higher growth performance. The stocking fish size of 34.14–34.71 g was found to be the best among the three treatments regarding growth performance and economic return. As a result, except for T1 and T2 at a rural site and T1 at a semi-urban site, all of the treatments had negative allometry (b < 3.0), indicating that larger-sized fish and the rural site of the river are more suitable for cage culture. The rural site was found to be more suitable, possibly due to less variation of water parameters, more natural foods, and less pollution. The cages with larger-sized fish stocked had a higher net present value (NPV); internal rate of return (IRR); benefit–cost ratio (BCR); and rate on return (ROI), indicating that cage culture with larger-sized fish stocked is economically viable in the riverine system. Therefore, stocking the larger-sized fish (T1) and rural site are more suitable for cage culture.