Viral infectious diseases rank among the leading causes of mortality globally. The rise of drug resistance mechanisms puts the effectiveness of all existing antimicrobial drugs at risk, several of which have become ineffective. Consequently, there is an acute need for novel antimicrobial agents. Host defense antimicrobial peptides (AMPs) are naturally occurring, evolutionarily conserved peptides that contribute to innate immunity and exhibit broad activity against viruses, bacteria, and fungi. They can also exert immunomodulatory and adjuvant activities by serving as chemotactic agents for immune cells and promoting cytokine and chemokine production. Vitamin D is a fat-soluble steroid hormone essential for regulating calcium and phosphorus metabolism to preserve bone homeostasis. Recent research has indicated that vitamin D has immunomodulatory effects on both the innate and adaptive immune systems, suggesting that it is a vital regulator of immunological homeostasis. Vitamin D stimulates the development of robust AMPs found in natural killer cells, monocytes, neutrophils, and epithelial cells of the respiratory tract. This chapter explains the evidence suggesting that vitamin D can reduce viral survival and replication by inducing AMPs.