Rosacea is a chronic inflammatory skin disorder characterized by facial erythema, papules, pustules, and telangiectasia, affecting approximately 5.5% of the global population. Current treatments, primarily topical and oral antibiotics and anti-inflammatories, often show limited efficacy and may cause undesirable side effects, prompting the need for alternative therapies. Cannabidiol (CBD), a non-psychoactive component of Cannabis sativa, has shown promise as a therapeutic agent for rosacea due to its anti-inflammatory, antioxidant, and anti-apoptotic properties. CBD interacts with the endocannabinoid system, which plays a crucial role in cutaneous homeostasis. This study evaluated the efficacy of CBD, both alone and in combination with metronidazole (MET), in reducing inflammation and modulating immune responses in a rosacea-like mouse model. Our results demonstrated that both CBD and MET significantly inhibited redness, epidermal thickness, and mast cell infiltration, with their combination being more effective. Mechanistic analyses revealed that the therapeutic effect of CBD is associated with the suppression of key inflammatory regulators in the MAPK signaling pathway, particularly the ERK, JNK, and p38 pathways. CBD treatment also led to a significant reduction in pro- inflammatory cytokines and chemokines, indicating immune modulation. These findings suggest that CBD, especially in combination with MET, may represent a novel therapeutic option for rosacea and offer a scientific basis for its clinical application in managing inflammatory skin conditions. [BMB Reports 2025; 58(8): 357-363].