Physical exercise can be effective in preventing or ameliorating various diseases, including diabetes, cardiovascular diseases, neurodegenerative diseases, and cancer. However, not everyone may be able to participate in exercise due to illnesses, age-related frailty, or difficulty in long-term behavior change. An alternative option is to utilize pharmacological interventions that mimic the positive effects of exercise training. Recent studies have identified signaling pathways associated with the benefits of physical activity and discovered exercise mimetics that can partially simulate the systemic impact of exercise. This review describes the molecular targets for exercise mimetics and their effect on skeletal muscle and other tissues. We will also discuss the potential advantages of using natural products as a multi-targeting agent for mimicking the health-promoting effects of exercise.