This study aimed to investigate the effect of A. sobria infection on the gills and skin histopathology of the Nile tilapia reared in biofloc technology (BFT) compared to a clear water system (CWS). The Nile tilapia fish were divided into four groups: two groups in BFT (control group without infection (BFTC) and A. sobria infected group (BFTT)) and the other two in CWS (control group without infection (CWSC) and A. sobria infected group (CWST)). The infection was done by I/P (intraperitoneal) injection of 0.1 ml of 1.5×10⁸ CFU/ml of A. sobria. The gills histopathology of CWST group showed moderate to severe histopathological alterations; congestion of lamellar blood vessels, mononuclear and eosinophilic leukocytic infiltration, and sloughing of lamellar epithelium; while it only showed mild epithelial hyperplasia in the BFTT group. Skin hyperemia and tail rot were observed grossly without any histopathological alterations in the skin of both BFTT and CWST groups. Total heterotrophic bacterial count in culture water was higher in BFTC group, nevertheless, its count in the fish gut was higher in CWSC group. In both BFTT and CWST groups, after infection, a decrease was detected in the total heterotrophic bacterial count in culture water and fish gut, while it was still higher in BFTT group. At the early stage of A. sobria infection, the gills are severely affected, and its injury may not be observed, paving the way for other diseases. Meanwhile, the skin may show hyperemia grossly without any histopathological alterations. Results of the current study showed that the biofloc system proved its capacity of protecting the gills of the Nile tilapia against A. sobria infection.