<b><i>Introduction:</i></b> The low-intensity pulsed ultrasound (LIPUS) is one of the popular treatment modalities allowing to boost the proliferation, differentiation, and migratory activity of cells, which might be a powerful strategy for anti-aging. Seeking a novel setup for LIPUS would benefit the development of ultrasound therapeutics. <b><i>Methods:</i></b> Here, we proposed a novel underwater exposure setup of LIPUS. C57BL/6 mice were reared in the designated age-groups, which consisted of a middle-aged group (12–14 months) and an old-age group (20–23 months). The age-related changes of body composition, imbalance of energy supply and demand, imbalance of signal network maintaining internal stability, and representative phenotypes of neurodegeneration and neuroplasticity with the presence and absence of underwater LIPUS in middle-aged and aged groups were evaluated. <b><i>Results:</i></b> The results showed that there were obvious aging changes, imbalance of energy supply and demand, imbalance of signal network maintaining homeostasis, neurodegeneration, and damage of neural plasticity in the middle-aged and aged group with or without the LIPUS. Although middle-aged group and aged group responded differently to LIPUS, they mostly generated positive results in relieving bone loss, improving ovarian structure, regulated immune system, and enhanced endurance ability, which should have declined over age. <b><i>Discussion:</i></b> These findings indicate that underwater extracorporeal LIPUS exposure could be employed as single or combined anti-aging strategies that generated positive outcomes against the process of aging.