A 10-week feeding trial was conducted to examine the effect of dietary sacha inchi meal (SIM) as a soybean meal (SBM) replacer on growth performance, feed utilization, whole-body fatty acid composition, blood biochemistry, and histological changes in red hybrid tilapia, Oreochromis niloticus × O. mossambicus. Five isonitrogenous and isolipidic diets were formulated with 0 (control diet), 110, 220, 320, and 420 g/kg replacement of SBM with SIM (referred to as SIM0‒420). Each diet was randomly assigned to one of five fish groups in a 100 L indoor tank (n = 15 each, average initial weight 9.36 ± 0.02 g) with four replicates. During the last 2 weeks of the feeding trial, 5 g/kg chromic oxide (Cr2O3) was added to the diet to determine the apparent digestibility coefficient (ADC). The results showed that SIM inclusion significantly increased growth performance, feed utilization, and ADC of dry matter in a quadratic manner with the highest final weight observed in the SIM110 group. Survival rates were not significantly affected by SIM inclusion levels (P > 0.05). The amount of n-3 fatty acids in the whole-body fish, particularly that of C18:3n-3, was linearly and quadratically increased (P < 0.001) with increasing dietary SIM inclusions. Total cholesterol and triglycerides (TGs) were linearly and quadratically decreased in the fish fed the SIM inclusion diets (P < 0.05), but no linear or quadratic effects of dietary treatments were observed on levels of total protein, albumin, globulin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). Liver histology showed a significant increase in cytoplasmic vacuolization with increasing SIM inclusion in diets, and fish fed the SIM420 diet showed hepatocyte swelling and displacement of hepatocyte nuclei toward the periphery. Similarly, intestine histology detected a significant linear reduction in villi height and villi thickness with increasing level of dietary SIM (P < 0.001). Overall, the present study indicates that SIM protein can totally replace soybean protein in tilapia diets, while high SIM inclusion results in histological abnormalities. In particular, SIM110 replacement can improve growth without any adverse effects in biochemical parameters, digestibility, and histological changes.