Stress is generally defined as a homeostatic disruption from actual or implied threats and alters the homeostatic balance of different body organs, such as gastrointestinal function and the hypothalamic-pituitary-adrenal axis (HPA), inducing the release of glucocorticoid hormones. Stress is also known to be a risk factor for the development of depression and anxiety. However, until today there are no suitable therapies for treating of stress. The aim of this study was to explore the protective effect of Colomast®, a new preparation containing Adelmidrol, an enhancer of physiological of palmitoylethanolamide (PEA), and sodium hyaluronate in an animal model of immobilization stress. Acute restraint stress (ARS) was induced in mice by fixation for 2 h of the four extremities with an adhesive tape and Colomast® (20 mg/kg) was administered by oral gavage 30 min before the immobilization. Colomast® pre-treatment was able to decrease histopathological changes in the gastrointestinal tract, cytokines expression, neutrophil infiltration, mast cell activation, oxidative stress, as well as modulate nuclear factor NF-kB and apoptosis pathways after ARS induction. Moreover, Colomast® was able to restore tight junction in both ileum and hippocampus and cortex. Additionally, we demonstrated that Colomast® ameliorated depression and anxiety-related behaviours, and modulate inflammatory and apoptosis pathways also in brain after ARS induction. In conclusion, our results suggest Colomast® to be a potential approach to ARS.