Cellular senescence is a state of stable growth arrest and a desired outcome of tumor suppressive interventions. Treatment with many anti‐cancer drugs can cause premature senescence of non‐malignant cells. These therapy‐induced senescent cells can have pro‐tumorigenic and pro‐disease functions via activation of an inflammatory secretory phenotype (SASP). Inhibitors of cyclin‐dependent kinases 4/6 (CDK4/6i) have recently proven to restrain tumor growth by activating a senescence‐like program in cancer cells. However, the physiological consequence of exposing the whole organism to pharmacological CDK4/6i remains poorly characterized. Here, we show that exposure to CDK4/6i induces non‐malignant cells to enter a premature state of senescence dependent on p53. We observe in mice and breast cancer patients that the CDK4/6i‐induced senescent program activates only a partial SASP enriched in p53 targets but lacking pro‐inflammatory and NF‐κB‐driven components. We find that CDK4/6i‐induced senescent cells do not acquire pro‐tumorigenic and detrimental properties but retain the ability to promote paracrine senescence and undergo clearance. Our results demonstrate that SASP composition is exquisitely stress‐dependent and a predictor for the biological functions of different senescence subsets. Synopsis Pharmacological CDK4/6 inhibitors lead to premature senescence in culture and in vivo. CDK4/6 inhibitors‐induced senescence is p53‐dependent and not associated with the detrimental pro‐inflammatory secretory phenotype, SASP. Exposure to pharmacological CDK4/6 inhibitors (CDK4/6i) causes premature senescence. CDK4/6i‐induced senescence is dependent on p53. CDK4/6i‐induced senescence is well tolerated in vivo. CDK4/6i‐induced senescent cells exhibit a p53‐associated secretory phenotype (PASP) but lack the NF‐kB‐associated secretory phenotype (NASP). While senescence‐linked inflammatory phenotypes caused by classical cancer drugs can be pro‐tumorigenic, senescence induced by CDK4/6 inhibitors lacks NF‐kB‐associated secretory phenotypes and is well tolerated in vivo.