The growing interest in senolytic therapy approaches designed to identify and clear dysfunctional senescent cells has opened new possibilities in longevity science. As researchers look for ways to elevate the effectiveness of senolytic strategies, mitochondrial-derived peptides (MDPs) like MOTS-c and Humanin are emerging as compelling candidates. These naturally occurring peptides play critical roles in cellular stress response, mitochondrial communication, and metabolic regulation, offering unique advantages that may synergize with senolytic pathways. In current studies, senolytic therapies focus on removing cells that drive inflammation, oxidative stress, and tissue deterioration. Yet, clearing senescent cells alone may not fully restore cellular health. This is where MOTS-c and Humanin may provide added value. MOTS-c has been noted for its influence on metabolic homeostasis, AMPK activation, and improved cellular resilience factors crucial for recovery after senescent cell clearance. Humanin, on the other hand, appears to offer protective benefits against mitochondrial dysfunction and apoptotic signaling, potentially supporting healthier neighboring cells as senolytics do their job.