Microplastics (MPs) and antibiotics (ATs) accumulating in Qinghai Lake threaten aquatic health, yet their impact on Gymnocypris przewalskii (G.przewalskii) remains unclear.This multi-omics study investigated polypropylene MPs (PP-MPs) and sulfonamide antibiotics (SGD) on G.przewalskii. Groups included control group (C), single exposure groups (1 g/L SGD, 1 mg/L PP-MPs, 5 mg/L PP-MPs), and co-exposure groups (1 mg/L PP-MPs + 1 g/L SGD, 5 mg/L PP-MPs + 1 g/L SGD) exposed for 28 days. Using 16S rRNA sequencing, UHPLC, and MS/MS, we analyzed changes in the intestinal microbiota, metabolome, and transcriptome of G. przewalskii. Compared to control gruop, intestinal microbiota alpha diversity changed significantly in all treatments. The SGD group decreased notably, while co-exposure groups (SPL) showed significantly lower alpha diversity than single exposures. SPL groups exhibited higher beta diversity than controls and single exposures. In SPL, genera like Legionella, Fusobacterium, Phascolarctobacterium, and Bacteroides decreased, whereas Shinella, Lactobacillus, and Prevotella increased. Differential metabolites and genes decreased with rising concentrations across exposure groups. Most metabolites enriched in the ABC transporter pathway. Differentially expressed genes primarily enriched in carbon metabolism and cytochrome P450 pathways. Correlation analysis identified pathways like Neisseriaceae and Acinetobacter affecting Bilirubin in the gut, which in turn influenced liver genes LOC107556838, LOC109072261 and notum1a. This demonstrated G. przewalskii adaptation to PP-MPs and SGD through the gut-live. The study provides a scientific basis for protecting G. przewalskii and assessing health risks of MPs and ATs to aquatic ecosystems on the Qinghai-Tibet Plateau.