Insect meal can be a promising nutrients source in aquafeed, replacing expensive, scarce or unsustainable foods however; molecular mechanisms behind its role on fish growth remain unknown. From this point, the impact of partial or total replacement of fish meal protein with defatted black soldier larvae meal (PD-BSLM) on Nile tilapia’s performance, body composition, expression of genes related protein and fatty acids transporters and immunity and economic efficiency was evaluated. A total of 500 Nile tilapia (17.9 ± 0.3 g) was distributed into 4 groups: control fed basal diet with 10% fish meal; the other 3 groups were fed basal in which fish meal was replaced by 25, 50 and 100% of PD-BSLM for 12-weeks. The results described that dietary inclusion of PD-BSLM had no negative impact on Nile tilapia’s growth rate, feed conversion ratio, protein utilization and nutrient digestibility even after 100% replacement. Body fat content was significantly decreased with increasing PD-BSLM levels. Amino acids analysis of fish body showed that replacement of fish meal with 100% PD-BSLM has a slight change on its lysine content. Interestingly, lysozymes, IgM and nitric oxide levels were significantly enhanced in group fed PD-BSLM at 100% replacement level. Transcriptomics profile of genes encoding amino acids (SLC3A1- SLC6A19) and peptides transporters (SLC15a1a-SLC15a1b-SLC15a2) revealed no negative effect in response to PD-BSLM. Moreover, mRNA expression of genes controlling fat transportation and metabolism (FABP-2, PPAR-α and PPAR-β) was up-regulated in groups fed higher PD-BSLM levels. Remarkably, mRNA expression of proinflammatory cytokines (IL-1β gene TNF-α) was down-regulated and anti-inflammatory cytokines (IL-10) was upregulated at higher PD-BSLM levels. Therefore, our study reported that replacement of fish meal with PD-BSLM up to 100% had a positive modulating effect on the expression of protein and fat transporters that can explain a non adversely affected growth performance of Nile tilapia. Besides, the higher inclusion levels of PD-BSLM can boost immunity of Nile tilapia as well as increased the economic efficiency.