Cellular senescence is a hallmark of aging, it is a permanent state of cell cycle arrest induced by cellular stresses. During the aging process, senescent cells (SCs) increasingly accumulate in tissues, causing a loss of tissue-repair capacity because of cell cycle arrest in progenitor cells and produce proinflammatory and matrix-degrading molecules which are known as the senescence-associated secretory phenotype (SASP), and thereby contribute to the development of various age-related diseases. Genetic evidence has demonstrated that clearance of SCs can delay aging and extend healthspan. Senolytics, small molecules that can selectively kill SCs, have been developed to treat various age-related diseases. In recent years, emerging natural compounds have been discovered to be effective senolytic agents, such as quercetin, fisetin, piperlongumine and the curcumin analog. Some of the compounds have been validated in animal models and have great potential to be pushed to clinical applications. In this review, we will discuss cellular senescence and its potential as a target for treating age-related diseases, and summarize the known natural compounds as senolytic agents and their applications.