The introduction of sodium-glucose cotransporter-2 (SGLT2) inhibitors and incretin-based therapies has transformed the management of obesity, type 2 diabetes, heart failure, and chronic kidney disease by delivering substantial metabolic, cardiovascular, and renal benefits. However, their effects on skeletal muscle have become a growing area of interest. While SGLT2 inhibitors induce modest weight loss, their catabolic metabolic effects have prompted questions regarding skeletal muscle preservation, particularly in individuals with limited physiological reserve. Conversely, the profound weight loss achieved with incretin-based therapies has raised concerns about accompanying reductions in lean tissue and their potential functional consequences. In this narrative review, we critically evaluate the available evidence regarding the effects of these therapeutic classes on skeletal muscle, integrating findings from randomized controlled trials, observational studies, systematic reviews, and mechanistic investigations. We compare their distinct biological mechanisms; summarize clinical evidence on changes in muscle quantity, quality, strength, and physical performance; and discuss their implications for older adults; individuals with frailty, sarcopenia, or sarcopenic obesity; and patients with heart failure or chronic kidney disease. Overall, current evidence indicates that both SGLT2 inhibitors and incretin-based therapies preferentially reduce adipose tissue, whereas the accompanying reductions in lean tissue are generally proportional to the magnitude of weight loss. Importantly, reductions in lean tissue should not be equated with treatment-induced sarcopenia, as current evidence does not consistently demonstrate clinically meaningful impairment in muscle strength or physical performance. Nevertheless, the populations most susceptible to skeletal muscle dysfunction remain underrepresented in clinical trials. We discuss a phenotype-based approach that integrates skeletal muscle health into therapeutic decision-making and outline practical strategies-including resistance exercise, adequate protein intake, and individualized monitoring-to preserve muscle function during treatment. Future research should prioritize standardized functional outcomes and dedicated studies in vulnerable populations to enable precision cardiorenal-metabolic medicine.