Antiretroviral drugs have dramatically improved the prognosis of HIV‐infected patients, with strikingly reduced morbidity and mortality. However, long‐term use can be associated with signs of premature aging. Highly active antiretroviral therapy generally comprises two nucleoside reverse transcriptase inhibitors (NRTIs), with one of three additional antiretroviral drug classes, including protease inhibitors (PIs). One commonality between mitochondrial dysfunction (induced by NRTIs) and defects in lamin A (induced by PIs) is they can cause or accelerate cellular senescence, a state of essentially irreversible growth arrest, and the secretion of many bioactive molecules collectively known as the senescence‐associated secretory phenotype (SASP). We hypothesized that senescent cells increase following treatment with certain HIV therapies. We compared the effects of two distinct HIV PIs: ritonavir‐boosted atazanavir (ATV/r) and ritonavir‐boosted darunavir (DRN/r), used in combination treatments for HIV infection. Upon ATV/r, but not DRN/r, treatment, cells arrested growth, displayed multiple features of senescence, and expressed significantly upregulated levels of many SASP factors. Furthermore, mice receiving sustained ATV/r treatment showed an increase in senescent cells and age‐related decline in physiological function. However, removing treatment reversed the features of senescence observed in vivo and cell culture. Given how these features disappeared with drug removal, certain features of senescence may not be prognostic as defined by an irreversible growth arrest. Importantly, for patients that are treated or have been treated with ATV/r, our data suggest that switching to another PI that does not promote premature aging conditions (DRN/r) may improve the associated age‐related complications. Patients infected with HIV are at increased risk for multiple diseases of aging. Here, Kuehnemann et. al. show that treating cells and mice with protease inhibitors (PIs) used in antiretroviral therapies for HIV induces many characteristics of cellular senescence. Surprisingly, senescent phenotypes triggered by PI treatment were reversed after removal of the drug, and treated mice regained lost physiological function. These findings suggest that intermittent treatment or switching to therapies that do not cause senescence could reduce PI‐induced premature aging.