In light of current knowledge on the role of reactive oxygen species and other oxidants in skin diseases, it is clear that oxidative stress facilitates inflammation and is an important factor involved in skin diseases, i.e., acne. Taking into consideration the fact that some Cotoneaster plants are valuable curatives in skin diseases in traditional Asian medicine, we assumed that thus far untested species C. hsingshangensis and C. hissaricus may be a source of substances used in skin diseases. The aim of this study was to evaluate the antioxidant, anti-inflammatory, antimicrobial, and cytotoxic activities of their various extracts. LC-MS analysis revealed the presence of 47 compounds (flavonoids, phenolic acids, coumarins, sphingolipids, carbohydrates), while GC-MS procedure allowed for the identification of 42 constituents (sugar derivatives, phytosterols, fatty acids, and their esters). The diethyl ether fraction of C. hsingshangensis (CHs-2) exhibited great ability to scavenge free radicals and good capacity to inhibit cyclooxygenase-1, cyclooxygenase-2, lipoxygenase, and hyaluronidase. Moreover, it had the most promising power against microaerobic Gram-positive strains, and importantly, it was non-toxic toward normal skin fibroblasts. Taking into account the value of the calculated therapeutic index (>10), it is worth noting that CHs-2 can be subjected to in vivo study and constitutes a promising anti-acne agent.