A small GTPase, Cdc42 is evolutionarily one of the most ancient members of the Rho family, which is ubiquitously expressed and involved in a wide range of fundamental cellular functions. The crucial role of Cdc42 includes regulation of the actin cytoskeleton, cell polarity, morphology and migration, endocytosis and exocytosis, cell cycle, and proliferation in many different cell types. Many studies have provided compelling yet contradicting evidence that Cdc42 dysregulation plays an important role in cellular and tissue aging. Furthermore, Cdc42 is a critical factor in the development and progression of aging-related pathologies, such as neurodegenerative and cardiovascular disorders, diabetes type 2, and aging-related disorders of the joints and bones, and the inhibition of the Cdc42 demonstrates potentially significant therapeutic and anti-aging effects in animal models of aging and disease. However, regulation of Cdc42 expression and activity is very complex and depends on many factors, such as the origin and complexity of the tissues, hormonal status, etc. Therefore, this review is focused on current advances in understanding the underlying cellular and molecular mechanisms associated with Cdc42 activity and regulation of senescence in different cell types since they may provide a foundation for novel therapeutic strategies and targeted drugs to reverse the aging process and treat aging-associated disorders.