Abstract: Polypropylene microplastics (PP-MPs) and sulfaguanidine (SGD) have been detected in the water, sediment, and aquatic organisms of Qinghai Lake. In order to investigate the toxic effects of combined exposure to PP-MPs and SGD on the Gymnocypris przewalskii, we divided the fish into six groups: a control group (C), three singly exposed groups (1 g/L SGD, 1 mg/L PP-MPs, and 5 mg/L PP-MPs, labeled as S, PL, and PH), and two combined exposed groups (1 mg/L PP-MPs+1g/L SGD and 5 mg/L PP-MPs+1 g/L SGD, labeled as SPL and SPH) for a 28d exposure treatment. The enrichment characteristics of PP-MPs in different tissues were determined using tissue acid digestion, and the toxic effects were evaluated through hematoxylin-eosin staining, as well as measurements of intestinal digestive enzyme and liver oxidative enzyme activities. The growth index analysis showed that single and combined exposure to PP-MPs and SGD had little effect on the body length and weight of the G. przewalskii. However, PP-MPs were detected in the gills, intestines, liver, and brain tissues of the exposed groups, with higher concentrations in the gills and intestines increasing with exposure time. Histological analysis revealed that as PP-MPs accumulated, the length of intestinal villi and the villus height to crypt depth ratio decreased. In the liver tissue, cell nuclear shrinkage and disintegration, reduced cytoplasm, and infiltration of inflammatory cells were observed. The damage was more severe in the PH group compared to the PL group and was more pronounced in the combined exposure group than that in the single exposure group. Enzyme activity measurements indicated an increasing trend in intestinal lipase activity in the exposed groups compared to the control group, while amylase activity decreased, and there was no significant change in pancreatic enzyme activity. Hydrogen peroxide enzyme activity in liver tissue significantly increased, while superoxide dismutase activity was significantly higher in the S group and the SPL and SPH combined groups. In summary, both single and combined exposure to PP-MPs and SGD resulted in the enrichment of microplastics in various tissues of the G. przewalskii, causing damage to intestinal and liver tissues and oxidative stress reactions. The severity of the damage increased with higher concentrations of microplastics, and combined exposure was more severe than single exposure. This study provides a theoretical basis for exploring the toxicological harm of coexisting microplastics and other pollutants on G. przewalskii and is of great significance for assessing potential risks to the Qinghai Lake ecosystem.