Candida albicans (C. albicans) is an opportunistic pathogen that can cause fungal infection at different sites. At present, drugs for the treatment of C. albicans is single. With the irrational use of clinical drugs, drug resistance of C. albicans is becoming increasingly serious. Histatins 5 (Hst-5) is the most abundant antimicrobial peptide (AMP) secreted from oral saliva. As the first defense line of the host, it has strong antibacterial activity against C. albicans. Its mechanism of action is different from that of traditional antifungal drugs and other antimicrobial peptides, which involves a variety of transport proteins on the surface of C. albicans, MAPK pathway, and various metal ions in vitro. With the in-depth study of Hst-5, it is found that a variety of derivative peptides of Hst-5 (K11R-K17R, P-113Tri, etc.) can play a more vital role in improving antimicrobial efficacy. Therefore, it is particularly important to study the antimicrobial mechanism of Hst-5 and its derived peptides in C. albicans, which will provide a new strategy for the therapy of clinical fungal infections at present.