Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, are directly involved in the degradation of the extracellular matrix preceding uncontrolled cancer growth and metastasis. For these reasons, MMPs are considered key therapeutic targets in the development of cancer treatments. Acknowledged for its prophylactic effects against various diseases including cancer, physical exercise has been reported to boost immune systems, enhance endogenous defense mechanisms managing oxidative stress, and MMP regulation. Despite its benefits, patients with compromised capacity for physical activity due to injuries and frailty are often unable to take advantage of them. As a possible solution for this problem, the alternative therapeutic approach of exercise mimetics have been gaining traction through pharmacological interventions. Exercise mimetics are pharmacological agents that mimic the molecular and physiological benefits of physical exercise without requiring actual physical activity. Recent studies have indicated the potential of these exercise mimetics as potential cancer treatment agents. In this study, the potential anti-cancer and anti-metastatic effects of six selected exercise mimetics (i.e., AICAR, Icariin, Berberine, Betaine, GW501516, and Metformin) were investigated. These compounds (i) inhibited MMP-2/9 activity by interacting with the active site and/or allosteric sites, (ii) downregulated MMP-2/9 by influencing MAPK and STAT3 signaling pathways, and (iii) exhibited anti-cancer activity against lung cancer and cervical cancer cells. Among the exercise mimetics, Icariin and Berberine showed the most potent inhibitory capacities against both the activity and expression of MMP-2/9 in cancer cells. These findings suggest the potential of exercise mimetics as targeted cancer therapeutics, offering innovative approaches for managing MMP-driven cancer progression and metastasis. These findings suggest the potential of exercise mimetics as innovative candidates for cancer therapeutics, offering creative approaches for managing MMP-driven cancer progression and metastasis.