<p>Cellular senescence is characterized by a state of stable proliferation arrest which ultimately leads to decline in the regenerative potential of cells, tissues and organ. Several factors like oxidative stress, DNA damage, neuroinflammation, and altered proteostasis mark the onset of cellular senescence. A growing body of evidence highlights a strong association between cellular senescence and the development of neurodegenerative disorders, where the accumulation of senescent cells contribute to chronic inflammation, tissue dysfunction, and progressive neuronal degeneration. Despite significant advances in understanding brain aging, effective therapeutic strategies targeting these mechanisms remain limited. Over the years, targeting cellular senescence has emerged as a promising strategy in the development of senotherapeutics for age-associated neurodegenerative diseases. Stem cells and their acellular derivatives, such as the secretome, extracellular vesicles, and mitochondria, have recently emerged as promising senotherapeutic candidates. As evidenced from previous reports, cell-free components of stem cells may confer senotherapeutic benefits by delivering bioactive molecules and maintaining tissue microenvironmental homeostasis to rejuvenate the senescent cells. However, previous reviews have predominantly focussed on senotherapeutics and role of stem cells as antiaging agents. There remains a lack of integrated understanding of their role in modulating brain aging and neurodegeneration. In this review, we discuss the mechanistic role of cellular senescence in neurodegeneration contributing to brain aging and highlight emerging insights into stem cell and its acellular products as potential senotherapeutic strategies. Furthermore, we have highlighted some therapeutic strategies based on acellular products of stem cells in for combating age-associated brain dysfunction. Our manuscript uniquely provides a comprehensive essay on mechanistic insights, therapeutic convergence, and translational implications.</p>