In assigning priorities, skin infectious diseases are frequently classified as minor when compared to infectious diseases of high mortality rates, such as tuberculosis or HIV. However, skin infections are amongst the most common and prevalent diseases worldwide. Elderly individuals present an increased susceptibility to skin infections, which may develop atypical signs and symptoms or even complicate pre-existing chronic disorders. When the skin fails to correct or inhibit the action of certain pathogenic microorganisms, biomolecules endowed with antimicrobial features are frequently administered topically or systemically to assist or treat such conditions. (1) Antibiotics, (2) antimicrobial peptides, or (3) natural extracts display important features that can actively inhibit the propagation of these pathogens and prevent the evolution of infectious diseases. This review highlights the properties and mechanisms of action of these biomolecules, emphasizing their effects on the most prevalent and difficult to treat skin infections caused by pathogenic bacteria, fungi, and viruses. The versatility of biomolecules’ actions, their symbiotic effects with skin cells and other inherent antimicrobial components, and their target-directed signatures are also explored here.