Astaxanthin is a naturally occurring compound that possesses immunomodulatory properties. The results of our previous investigation indicated that astaxanthin has the potential to augment the anticancer effectiveness of the targeted medication sorafenib. However, the precise molecular mechanism underlying this phenomenon remains unclear. H22 tumor-bearing mice were treated with sorafenib at 30 mg kg-1 per day and their diet was supplemented with 60 mg kg-1 day-1 astaxanthin orally for a period of 18 days. The study revealed that the addition of astaxanthin to the diet facilitated the transition of tumor-associated macrophages from the M2 phenotype to the M1 phenotype. The application of astaxanthin resulted in an augmentation of CD8+ T cell infiltration within the tumor microenvironment through the activation of the CXCL9/CXCR3 signaling axis. Astaxanthin was found to enhance the production of cytokines that possess antitumor properties, including Granzyme B. Furthermore, the administration of astaxanthin resulted in alterations to the intestinal microbiota in H22-bearing mice, leading to the growth of bacteria that possess anti-tumor immune properties, such as Akkermansia. The findings of these studies indicate that astaxanthin has the potential to augment the immune response against tumors when used in conjunction with sorafenib. These studies offer a novel framework for the advancement of astaxanthin as an immunomodulatory agent and a dietary supplement for individuals with tumors.