Frailty is a complex condition that emerges from dysregulation in multiple physiological systems. Increasing evidence suggests the potential role of age-related energy dysregulation as a key driver of frailty. Exercise is considered the most efficacious intervention to prevent and even ameliorate frailty as it up-tunes and improves the function of several related systems. However, the mechanisms and molecules responsible for these intersystem benefits are not fully understood. The skeletal muscle is considered a secretory organ with endocrine functions that can produce and secrete exercise-related molecules such as myokines. These molecules are cytokines and other peptides released by muscle fibers in response to acute and/or chronic exercise. The available evidence supports that several myokines can elicit autocrine, paracrine, or endocrine effects, partly mediating inter-organ crosstalk and also having a critical role in improving cardiovascular, metabolic, immune, and neurological health. This review describes the current evidence about the potential link between energy metabolism dysregulation and frailty and provides a theoretical framework for the potential role of myokines (via exercise) in counteracting frailty. It also summarizes the physiological role of selected myokines and their response to different acute and chronic exercise protocols in older adults.