The aim of this study was to elucidate the mechanism of action of astaxanthin in reversing insulin resistance in mice with type 2 diabetes mellitus (T2DM). In this study, a T2DM model was established by feeding a high-calorie diet, and the effect of astaxanthin on glucose tolerance and insulin resistance in T2DM mice was evaluated by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). The contents of tumor necrosis factor-α (TNF-α) and fructosamine (FRA) were determined by enzyme-linked immunosorbent assay (ELISA). Furthermore, the expressions of Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3) and nuclear factor κB (NF-κB) in mouse liver were detected by Western blot, and the role of inflammatory signaling in reversing insulin resistance by astaxanthin was explored under the guidance of network pharmacology analysis. It was found that astaxanthin significantly reduced blood glucose, TNF-α, and FRA levels, and enhanced islet function and alleviate insulin resistance in T2DM mice. Western blot results showed that astaxanthin significantly inhibited the phosphorylation of JAK2, STAT3 and NF-κB proteins. In summary, astaxanthin lowers blood glucose and reverses insulin resistance by inhibiting the JAK2/STAT3 and NF-κB signaling pathways.