Persistent luminescence phosphors (PLPs) can remain luminescent after excitation ceases and have been widely explored in bioimaging and therapy since 2007. In bioimaging, PLPs can efficiently avoid tissue autofluorescence and light scattering interference by collecting persistent luminescence signals after the end of excitation. Outstanding signal-to-background ratios, high sensitivity, and resolution have been achieved in bioimaging with PLPs. In therapy, PLPs can continuously produce therapeutic molecules such as reactive oxygen species after removing excitation sources, which realizes sustained therapeutic activity after a single dose of light stimulation. However, most PLPs are activated by ultraviolet or visible light, which makes it difficult to reactivate the PLPs in vivo, particularly in deep tissues. In recent years, excitation sources with deep tissue penetration have been explored to activate PLPs, including X-ray, γ-ray, and ultrasound. Researchers found that various inorganic and organic PLPs can be activated by X-ray, γ-ray, and ultrasound, making these PLPs valuable in the imaging and therapy of deep-seated tumors. These X-ray/γ-ray/ultrasound-activated PLPs have not been systematically introduced in previous reviews. In this review, we summarize the recently developed inorganic and organic PLPs that can be activated by X-ray, γ-ray, and ultrasound to produce persistent luminescence. The biomedical applications of these PLPs in deep-tissue bioimaging and therapy are also discussed. This review can provide instructions for the design of PLPs with deep-tissue-renewable persistent luminescence and further promote the applications of PLPs in phototheranostics, noninvasive biosensing devices, and energy harvesting.