Purpose <p>A systematic review was performed to assess the economic evaluation of sodium glucose transporters 2 (SGLT2) inhibitors vs GLP-1 receptor agonists (GLP-1RA) in treating type 2 diabetes.</p> Methods <p>The relevant studies were searched in PubMed, Web of Science, Scopus, Embase, and Cochrane from the inception date to February 20, 2025. The titles, abstracts, and full texts were independently evaluated and screened by two authors. Additionally, the economic evaluation studies were assessed independently by two authors.</p> Results <p>18 studies were included, evaluating oral semaglutide vs empagliflozin (<i>n</i> = 7), both oral semaglutide vs empagliflozin and subcutaneous semaglutide vs canagliflozin (<i>n</i> = 1), subcutaneous semaglutide vs empagliflozin (<i>n</i> = 4), liraglutide vs empagliflozin (<i>n</i> = 4), liraglutide vs dapagliflozin (<i>n</i> = 1), and subcutaneous semaglutide vs canagliflozin (<i>n</i> = 1).</p> Conclusion <p>The results showed that when patients were assumed to receive initial therapies until HbA1c exceeded the target level and then treatment was intensified to basal insulin, GLP-1RA was cost-effective compared to SGLT2 inhibitors (semaglutide vs empagliflozin and liraglutide vs dapagliflozin). Empagliflozin demonstrated cost-effectiveness when the treatment with either empagliflozin or semaglutide would have continued indefinitely. Compared with empagliflozin, liraglutide may not be a cost-effective treatment option for patients with T2D who were not well-controlled with metformin.</p>