Aquaculture development in Ghana is currently limited by inadequate supply of fingerlings and prohibitive cost of commercial feeds among other challenges. This study tested the feasibility of using low-cost feeds containing soybean meal instead of fishmeal for nursing Nile tilapia (Oreochromis niloticus) fry. Three isonitrogenous (~48% crude protein) and isoenergetic (~17 kJ/g) diets with increasing inclusions of soybean meal as partial replacements for fishmeal were formulated. A commercial fishmeal-based fry feed served as the control diet. Triplicate groups of 225 fish per tank (average initial weight: 2.09 ± 0.14 g) were stocked in a recirculating aquaculture system and fed the experimental diets for 21 days. Afterwards, we investigated the postprandial metabolism, nutrient digestibility, growth and gut histology in Nile tilapia fry. Simple economic analyses were also conducted to assess the cost-effectiveness of the diets used in the feed trial. The dietary inclusions of the soybean meal significantly reduced feed cost by ~43% relative to the control diet. The growth performance and feed utilization parameters did not vary significantly among the different treatments. The soybean diets elicited significant reductions in villi heights and goblet cell numbers, which corresponded with increasing dietary levels of soybean meal. This study confirms the potential of soybean meal as a partial replacement for fishmeal in Nile tilapia fry diets in terms of lower feed costs, fish growth performance, nutrient digestibility and postprandial nitrogenous excretions. The inclusion of soybean, however, affected negatively the gut integrity of the fry.