Enrofloxacin (ENR) and atrazine (ATZ) are common co-contaminants in marine environments. Although the immunosuppressive effects of ENR and the endocrine-disrupting properties of ATZ are well established, the combined effects of these pollutants on hepatotoxicity, particularly concerning the regulation of the hypothalamic-pituitary-thyroid (HPT) and gut-liver axes, remain poorly understood. In this study, Larimichthys crocea was exposed to ENR and ATZ at environmentally relevant concentrations, individually and in combination, to investigate the hepatotoxicity. Liver cell swelling, necrosis, oxidative stress, and elevated liver injury markers were observed, indicating hepatic damage, with co-exposure exacerbating liver injury. Decreased levels of thyrotropin-releasing hormone and thyroid-stimulating hormone, increased triiodothyronine and thyroxine, and altered expression of HPT axis-related genes demonstrated enhanced disruption of the HPT axis under co-exposure, which was strongly associated with oxidative stress and liver dysfunction. Molecular docking confirmed that ENR and ATZ inhibited thyroid hormone binding to target proteins, likely provoking the enhanced hepatotoxicity. Additionally, ATZ significantly intensified the intestinal bacterial disturbances induced by ENR, further aggravating hepatotoxicity through the gut-liver axis. This study is the first to reveal the increased risk associated with ENR and ATZ co-exposure, highlighting the need for attention to such co-contaminants.