Postbiotics are an emerging research interest in recent years, which shows that metabolites, lysate extracts, cell wall components and even culture supernatants of probiotics can also exhibit significant prebiotic effects. In this study postbiotic stress worry free concentration® (SWFC) were prepared from the composition of culture supernatant of Cetobacterium somerae and Lactococcus lactis. The positive effects of SWFC supplemented diets on the growth performance, skin mucus, liver and gut health, and intestinal microbiota profile of Cyprinus carpio fed with high fat diets were investigated. 180 C. carpio with an average body weight of (3.01 ± 0.01) g were selected and randomly divided into three groups. They were fed with one of the three experimental diets supplemented with SWFC of 0 (control), 0.2 and 0.3 g/kg for 98 days, afterwards indexes were detected. The results revealed that, addition of SWFC had no significant effect on growth performance of C. carpio, while it can improve the health of the fish remarkably. In addition, SWFC improved mucosal C3, T-AOC, SOD activities, and decreased lipid peroxidation product MDA level, which were notably better than those in the control group (P < 0.05). In terms of the liver health systems, C. carpio fed on the diet supplemented with 0.2 g/kg of SWFC, showed significant improvement of the liver injured by HFD and reduce the contents of serum ALT and AST, and liver TAG (P < 0.05; P < 0.01). The expression of inflammation-related and lipid synthesis genes revealed that SWFC0.2 group could noteworthy enhance antioxidant capacity, reduced the expression of pro-inflammatory factors (TNF-α, IL-1β) and lipid synthesis genes (ACC, FAS, PPAR-β, PPAR-γ), and up-regulated the expression of anti-inflammatory factors (TGF-β). Additionally, intestinal morphology arose inflammatory cell infiltration, while intestinal integrity was better in SWFC groups compared with the control. Furthermore, the contents of serum LPS and LBP were remarkably lower in the SWFC0.2 group compared with the control (P < 0.01). The mRNA expression of genes related to gut health indicated that SWFC supplementation noteworthy up-regulated the expression of antioxidant (Nrf2, CAT, GPX), immune (Hepcidin, IL-10) and tight junction protein-related (ZO-1, Occludin). Simultaneously, the results of GF-zebrafish showed that the relative expression of anti-inflammatory genes (IL-1β, TGF-β) and antioxidant related genes (Nrf2, HO-1) were significantly up-regulated in SWFC groups. Data on intestinal microbiota profile verified that, at the phylum level, the abundance of Fusobacteria was remarkably elevated in the SWFC groups (P < 0.05), whereas the abundance of Firmicutes was declined noteworthy in SWFC0.2 and SWFC0.3 compared to the control group (P < 0.05; P < 0.01) respectively. At the genus level, the abundance of Cetobacterium in the SWFC groups were notably higher than those in the control group (P < 0.05), while the Vibrio content in the SWFC groups was significantly decreased (P < 0.05). PCoA result indicated that the intestinal microflora of SWFC0.2 group was abundant and diverse. Our results elucidate that dietary supplementation of SWFC protects C. carpio from HFD induced inflammatory response and oxidative stress, ameliorate skin mucus, liver and gut health, and improve the gut microbiota balance. Therefore, SWFC could be considered as an improving-fish-health additive, when supplemented to aquatic animal feed. With regards to how SWFC regulates the immunity and inflammatory responses and which signal transductions are involved remains unclear and more scientific evidences are needed to address these issues.