Cellular senescence (CS) is a permanent arrest of cell growth and exit of the cell cycle. It is an important tumor suppression mechanism and has a key role in wound healing, tissue regeneration, and prevention of tissue fibrosis. Despite the short-term benefits of CS, accumulation of senescent cells has deleterious effects and is associated with several pathological age-related phenotypes. As Heat Shock Proteins (HSP) are associated with cyto-protection, their role in longevity and CS became a research interest. However, an overview of the relationship between HSP and CS in humans still lacks in the literature. To provide an overview of the current state of the literature, this systematic review focused on the role of HSP in the development of CS in humans. PubMed, Web of Science and Embase were systematically screened for studies on the relationship between HSP and CS in humans. A total of 14 articles were eligible for inclusion. The heterogeneity and lack of numerical reporting of outcomes obstructed the conduction of a meta-analysis. The results consistently show that HSP depletion results in increased CS, while overexpression of HSP decreases CS, whether in cancer, fibroblasts, or stem cell lines. This systematic review summarized the literature on the prospective role of HSP in the development of CS in humans.