Cellular senescence of adipose tissue-derived mesenchymal stromal cells (AD-MSCs) is associated with chronic low-grade inflammation, metabolic dysfunction, and impaired adipogenesis contributing to the development of obesity, insulin resistance, and the progression of age-associated diseases. The aim of this study was to develop a model of cellular aging based on AD-MSCs to study the senolytic efficacy of the natural fisetin preparation for the subsequent development of geroprotective therapeutic strategies. The senescent markers SA-β-gal, SASP factors, and cell cycle arrest markers p16, p21, and p53 were assessed in models of replicative and stress-induced aging of AD-MSCs. H₂O₂ was identified as the most effective inducer of AD-MSC cellular senescence in comparison with LPS. It has been shown in the model of H₂O₂-induced senescence of AD-MSCs that the proportion of SA-β-gal+ cells was 2.0 (0.7)% in non-stimulated AD-MSCs, 81.7 (12.1)% in H₂O₂-stimulated AD-MSCs, and 19.1 (5.2)% and 13.0 (3.2)% after short-term (24 h) and long-term (7 days) fisetin treatment, respectively, indicating that fisetin treatment was associated with a lower proportion of SA-β-gal+ cells. Fisetin treatment resulted in a statistically significant decrease in the secretion of MCP-1, especially during long-term incubation. IL-1β showed a significant decrease after 7 days of fisetin treatment compared to H₂O₂, but the effect at 24 h was only significant in the group of 7 days of fisetin treatment. Fisetin treatment was also associated with higher p53 and p21 concentrations. Thus, in the present study, a model of H₂O₂-induced cellular senescence of AD-MSCs was developed, which can be used to evaluate the geroprotective potential of senotherapeutic preparations; fisetin warrants further evaluation as a potential senotherapeutic agent in this model.