Adiponectin, a key adipokine primarily secreted by adipocytes, plays crucial roles in metabolic homeostasis and inflammation, exhibiting anti-diabetic, anti-atherogenic, and anti-inflammatory properties. Its various isoforms and signaling via receptors like AdipoR1, AdipoR2, and T-cadherin contribute to its diverse biological functions. Sepsis is a life-threatening syndrome triggered by a dysregulated host response to infection, leading to systemic inflammation, multi-organ failure, and high mortality, currently lacking specific treatments. Preclinical studies largely suggest a protective role for adiponectin, demonstrating that its deficiency exacerbates inflammation and endothelial dysfunction, while its administration or agonism improves outcomes in experimental sepsis models. Clinical findings, however, present a complex picture, with inconsistent correlations between adiponectin levels and sepsis outcomes reported, suggesting its potential as a dynamic biomarker influenced by disease stage, patient heterogeneity, and isoforms, rather than a simple prognostic factor. Notably, glucagon-like peptide-1 receptor agonists (GLP-1RAs), used in obesity and diabetes management, have been shown to increase adiponectin levels, linking metabolic therapies to potential sepsis immunomodulation. Consequently, targeting adiponectin signaling, either directly with adiponectin mimics like AdipoRon or indirectly via strategies like GLP-1RA administration, represents a promising therapeutic approach for sepsis. Harnessing the adiponectin axis holds potential for advancing precision medicine in critical care, necessitating further research into adiponectin-based interventions and synergistic metabolic therapies to improve sepsis outcomes.