Changes in intestinal microecology play a crucial role in the pathogenesis and progression of metabolic diseases. Lycium barbarum polysaccharide (LBP) and quinoa ultrafine powder diet is a promising sources of prebiotics. However, the potential synergistic effects of combining them as a microbiota-targeted dietary supplement to mitigate lipid accumulation in nonalcoholic fatty liver disease (NAFLD) remain unclear. Our study aims to provide evidence for the application food/nutrient synergy interventions in NAFLD management, and also to support the clarification of these mechanisms. Following 12 weeks of a high-fat diet (HFD)-inducing NAFLD and an 11-week intervention in rats, the combination of LBP and quinoa ultrafine powder significantly decreased hepatocyte lipid accumulation and improved lipid metabolism disorders compared with those using either LBP or quinoa ultrafine powder alone. The combination increased beneficial intestinal microbiota, such as Lactobacillus acidophilus, Roseburia, Ruminococcus 2, and Prevotella, promoting the production of short-chain fatty acids, notably butyric acid, and then activated AMP-activated protein kinase/sterol regulatory element-binding protein 1C/stearoyl-CoA desaturase 1 (AMPK/SREBP-1C/SCD-1) signaling. Combining LBP with quinoa ultrafine powder is a promising microbiota-targeted dietary supplement for ameliorating lipid disorders in NAFLD.