As an ecological disturbance, salinity changes substantially impact aquatic organism health. Gut microbiota plays a pivotal role in host health and exhibits heightened sensitivity to environmental salinity stress; however, the potential correlative mechanisms between gut microbiota dysbiosis triggered by salinity changes and host health remain unclear. The present study conducted a 4-week stress experiment to investigate the precise impact of gut microbiota on the inflammatory response in Scatophagus argus under different salinities (0 ‰ [hyposaline group, HO], 25 ‰ [control group, CT], and 40 ‰ [hypersaline group, HE]). Our results revealed that both HO and HE stress significantly changed the relative abundances of Gram-negative bacteria and the impairment of intestinal barrier function. Subsequently, the levels of lipopolysaccharide (LPS) in the serum exhibited a significant increase, and the expression levels of genes (tlrs, myd88, irak1, irak4, and traf6) involving TLRs/MyD88/NF-κB signaling pathway and pro-inflammatory cytokines (il-6, il-8, il-1β, and tnf-α) in the representative immune organs were significantly upregulated. Conversely, the abundance of the anti-inflammatory gene (tgf-β1) and its protein contents in serum were decreased. Transplantation of the gut microbiota from S. argus exposed to varying salinities into germ-free Oryzias latipes resulted in an enhanced inflammatory response. Our results suggested that both HO and HE stress increased the presence of Gram-negative bacteria and disrupted the intestinal barrier, leading to elevated serum LPS and subsequent systemic inflammation in fish. These findings provide innovative insights into the influence of salinity manipulation strategies on the health of aquatic organisms, contributing to the mariculture management in coastal areas.