The role of senescent cells has been implicated in various tissue dysfunction associated with aging, obesity, and other pathological conditions. Currently, most transgenic mouse models only target p16 Ink4a-highly-expressing (p16 high) cells. Here, we generated a p21-Cre mouse model, containing a p21 promoter driving inducible Cre, enabling us to examine p21 Cip1-highly-expressing (p21 high) cells, a previously unexplored cell population exhibiting several characteristics typical of senescent cells. By crossing p21-Cre mice with different floxed mice, we managed to monitor, sort, image, eliminate, or modulate p21 high cells in vivo. We showed p21 high cells can be induced by various conditions, and percentages of p21 high cells varied from 1.5 to 10% across different tissues in 23-month-old mice. Intermittent clearance of p21 high cells improved physical function in 23-month-old mice. Our study demonstrates that the p21-Cre mouse model is a valuable and powerful tool for studying p21 high cells to further understand the biology of senescent cells.