Introduction: Inflammatory bowel disease (IBD) is a chronic inflammatory condition affecting the gastrointestinal tract with a multifactorial etiopathology. It encompasses two main forms: Ulcerative Colitis and Crohn’s Disease. The challenge of managing chronic inflammatory conditions highlights the need for innovative technologies that can effectively reduce inflammation while simultaneously promote tissue healing. Low intensity pulsed ultrasound stimulation (LIPUS) is becoming a new promising therapeutic strategy in different fields. Furthermore, recent studies underlined the strong anti-inflammatory effect of this mechanical stimulation. Aim: We aim to highlight an anti-inflammatory modulation promoted by LIPUS at defined frequency (38 kHz) and intensity (150 mW/cm2) in a DSS-induced pre-clinical model of acute colitis. Methods: We employed single and multiple LIPUS sessions to evaluate its impact on the recovery phase of the animals. Clinical parameters, including body weight and disease activity index, were monitored, and colon length and plasma cytokine levels were measured at the endpoint. Results: Data from this study confirm LIPUS's beneficial effect, particularly after a single stimulation in the early recovery phase. We have observed a significant improvement in clinical parameters with a reduction in circulating’ pro-inflammatory cytokines such as of IL-1β, IFN-γ, MCP-1, G-CSF, MIP-1β and TNF-α after a single LIPUS session. Conclusions: Our in vivo experiments provide new insights into the anti-inflammatory effect of LIPUS, setting the stage for its possible application as adjuvant therapy in the context of IBD.