The overgrowth of Propionibacterium acnes and the subsequent inflammation possess critical roles during acne vulgaris development. Cath-HG, an antimicrobial peptide previously characterized for its antimicrobial, anti-inflammatory, human protease-regulating, LPS-binding, and platelet glycoprotein VI (GPVI) inhibitory properties, has not been studied in the context of acne vulgaris. Here, Cath-HG was found to show strong anti-bacterial activities against P. acnes by promoting agglutination of bacteria, inhibition of biofilm formation, and disruption of the bacterial membrane. It also suppressed reactive oxygen species (ROS) and sebum production induced by P. acnes in HaCaT cells and inhibited the enzymatic activity of lipases and hyaluronidase. Moreover, Cath-HG also bound to lipoteichoic acid (LTA) and significantly attenuated the production of inflammatory factors through Toll-like receptor 2 (TLR2) in RAW264.7 macrophages. Consistently, Cath-HG exhibited antimicrobial effects and exerted anti-inflammatory activity by suppressing the activation of the mitogen-activated protein kinase (MAPK) signaling pathway in a P. acnes-induced mouse model. Consequently, Cath-HG could be a promising candidate for treatment of acne vulgaris.