Dietary supplementation of Spirulina platensis at different levels (0% control, 2.5%, 5% and 10%) was evaluated to find out the effects on growth performance, digestive enzyme activities, humoral and skin innate immune responses and disease resistance in the great sturgeon (Huso huso). After 8 weeks of experimental trial, growth parameters, intestinal lactic acid bacteria count, protease and lipase activities were significantly high in 10% S. platensis fed group (P < 0.05). Similarly, in this group, respiratory burst activity of leucocytes and total protein of serum were also significantly high. Furthermore, supplementation of S. platensis at 5 or 10% exhibited higher serum IgM and lysozyme activity than the other experimental groups (P < 0.05). On the contrary, serum triglycerides and number of blood lymphocytes were lower in experimental groups than that of control group. Total proteins, lysozyme, protease and esterase, as well as in vitro bactericidal activity (against Streptococcus iniae, Yersinia ruckeri, Aeromonas hydrophila and Lactococcus garviea) were significantly high in skin mucus from fish fed 5% and 10% S. platensis, while, alkaline phosphatase was significantly high in fish fed 10% S. platensis (P < 0.05). Further, fish infected with Streptococcus iniae bacteria increased mortality, but it was alleviated by a diet supplemented with S. platensis. The present results demonstrate that this dietary supplementation with S. platensis (mainly at 10% level) could be useful for maintaining the overall health status of great sturgeon.