A 90-day experiment was carried out to study the influence of biofloc system on water quality, growth, feed utilization, survivability, bacteria in fish gut, and physiological and immunological responses of thin-lipped mullet (Liza ramada). Two treatments, clear water (CW) and biofloc (BFS), were each designed in triplicates. Both treatments were stocked with Liza ramada (mean weight of 1.18 ± 0.02 g). BFS group showed the highest final body weight, weight gain, average daily weight gain, and specific growth rate, the lowest feed conversion ratio, and the highest protein efficiency ratio and survivability. The proximate analysis of biofloc samples showed that percent crude protein and lipid were 26.17 and 7.75% respectively with the presence of essential minerals required for fish growth. The total body chemical composition of fish demonstrated improved crude protein and fat in Liza ramada stocked in BFS compared to CW. The highest total bacterial count and Bacillus number were recorded in the intestine of fish kept under BFS. Protease, lipase, and amylase levels significantly increased in fish stocked in BFS. The highest antioxidant activity was observed in fish kept under BFS treatment, while cortisol, alanine aminotransferase, and serum aspartate aminotransferase showed the lowest activity. Significantly high serum total protein, serum albumin, serum globulin, phagocytic activity, lysozymes, respiratory burst activity, and immunoglobulin M were observed in fish raised in BFS compared to CW. The intestinal histomorphometry examination showed a significantly high villi length and width, crypt depth, high number of intraepithelial lymphocytes, and goblet cells in BFS group. BFS resulted in a significantly up-regulation of the immune genes in the liver (IL-1β, TNF-α, IL-8, and IL-10) and the growth-related genes in the liver (IGF-1 and GH) compared to CW treatment. These results revealed that applying biofloc system in the rearing of Liza ramada resulted in many advantages including growth improvement, high survivability, enhanced activity of digestive enzymes, antioxidant system, immunological response, gut health, and decreased stress enzymes.