Diabetes mellitus represents a growing global health challenge, establishing oral antidiabetic drugs as a therapeutic class of paramount importance. Consequently, to ensure drug safety, therapeutic efficacy, and accurate therapeutic drug monitoring, robust, selective and highly reproducible analytical methods are indispensable. This review provides a comprehensive overview of instrumental analytical techniques developed between 1985 and 2026 for quantifying oral antidiabetic agents. Based on a literature search across major databases—including PubMed, ScienceDirect and Springer—we systematically evaluated the application of UV-VIS spectrophotometry, liquid chromatography, and advanced electroanalytical methods. The reviewed literature encompasses methodologies ranging from routine quality control of bulk powders and pharmaceutical formulations to complex bioanalytical and pharmacokinetic applications. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) emerged as the gold standard for precise bioanalysis due to its superior selectivity and sensitivity in complex biological matrices. Conversely, UV-VIS spectrophotometry and electrochemical methods remain highly relevant for cost-effective routine quality control in industrial manufacturing. Methodologies are categorized by drug therapeutic class, including biguanides, sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, meglitinides, highlighting key validation parameters such as linearity, accuracy, and limits of detection. Finally, this review outlines future directions in the field of antidiabetic drug quantification.