The interest in the use of phytochemicals and herbal medicines for the treatment of acne vulgaris has grown steadily over recent decades. The research on the secondary metabolites and biological properties of bearberry (Arctostaphylos uva-ursi (L.) Spreng.) has been intensified in recent years, but the range of bacterial strains tested, many of which are highly relevant to human health, remains very limited. Therefore, the aim of this study was to evaluate the chemical composition and the antioxidant, antimicrobial, and cytotoxic activities of water and ethanolic bearberry leaf extracts. Compared with the ethanolic extract, the water extract was characterized by higher concentrations of arbutin, hydroquinone, corilagin, and hyperoside and the absence of ursolic acid and oleanolic acid. However, it exhibited lower total phenolic content and reduced levels of penta-O-galloyl-β-d-glucose (PGG). The ethanolic extract of bearberry leaves showed higher antioxidant activity and the most favorable overall biological properties. The therapeutic index (TI) values for the water and ethanolic extracts, respectively, were as follows: Cutibacterium acnes ATCC 11827 (10.70; 21.57), Propionibacterium acnes PCM 2334 (10.70; 43.13), P. acnes PCM (5.33; 21.57), Staphylococcus aureus ATCC 25923 (10.70; 21.57), and S. epidermidis ATCC 12228 (5.33; 10.78). The present findings further support the medicinal and cosmetic use of A. uva-ursi and highlight its potential as a source of natural antibacterial agents for acne treatment.