Type 2 diabetes mellitus imposes substantial clinical and economic burdens, necessitating treatment strategies that balance clinical effectiveness and economic value. This study aimed to synthesize evidence regarding the cost-effectiveness of sodium-glucose cotransporter-2 inhibitors (SGLT2i) compared with other glucose-lowering therapies. A systematic literature review was conducted following the PRISMA 2020 guidelines, using Scopus as the primary database. Of the 243 records identified, 81 articles underwent further assessment, and 35 studies met the inclusion criteria. The findings indicated that SGLT2i were generally cost-effective, particularly compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, and standard or conventional care. However, comparisons with glucagon-like peptide-1 receptor agonists (GLP-1 RAs), metformin, and thiazolidinediones produced heterogeneous results, while direct comparative evidence against insulin remained limited. Differences in cost-effectiveness outcomes were influenced by economic modeling approaches, analytical time horizons, discount rates, evaluation perspectives, medication prices, willingness-to-pay thresholds, patient risk profiles, treatment pathways, and healthcare system characteristics. These findings suggest that SGLT2i offer substantial economic value in managing type 2 diabetes mellitus, although their relative cost-effectiveness varies across comparators and decision-making contexts. Future economic evaluations should incorporate locally relevant costs, long-term clinical outcomes, and healthcare system characteristics to support evidence-based treatment decisions and optimize resource allocation in diabetes care.