Jatropha platyphylla is a multipurpose and drought-resistant shrub, available in Mexico, locally known as ‘sangregrado’ and belonging to the family Euphorbiaceae. Its seeds are rich in oil and protein and do not contain the main toxin, phorbol esters present in other Jatropha species. Jatropha platyphylla kernel meal (JPKM) obtained after oil extraction contained 70–75% crude protein (CP); however, it contained phytate, lectin and trypsin-inhibitor. The levels of essential amino acids (except lysine) were higher in JPKM than in soybean meal (SBM). Using Nile tilapia (Oreochromis niloticus) fingerlings a 12-week experiment was conducted to evaluate the nutritional quality of the heated JPKM and compare with that of SBM and fishmeal. Fingerlings (15 fish; average weight 13.7 ± 0.21 g) were randomly distributed in three treatment groups with five replicates. Fish were fed three isonitrogenous diets (CP 36%): control diet containing fishmeal-based protein and two other diets replacing 62.5% fishmeal protein with JPKM (Jatropha group) and SBM (Soybean group). The growth performance, feed conversion ratio, protein efficiency ratio, protein productive and energy retention did not differ significantly among the three groups. A lower apparent lipid conversion was observed in the plant protein-fed group than in the control group. RBC count, haematocrit and blood glucose contents were higher in plant-protein fed groups than control group. Other haematological parameters (WBC count, haemoglobin, mean cell volume: calcium and sodium ions, total bilirubin and urea–nitrogen in the blood) and metabolic enzymes (alkaline phosphatase and alanine transaminase) activities in blood did not differ significantly among the three groups. The results from the present study established that JPKM is a promising and good quality protein source for Nile tilapia feed.