Herpes Simplex Virus (HSV) infections, caused primarily by HSV-1 and HSV-2, are among the most prevalent viral diseases worldwide, with recurrent manifestations that significantly affect quality of life. Therapeutic strategies include both topical and systemic interventions, each with distinct goals. This systematic review was conducted according to PRISMA guidelines. A comprehensive search of PubMed, Scopus, and Web of Science (2005–2025) identified studies evaluating topical or systemic treatments for HSV. Eligible studies included randomized controlled trials and observational studies reporting validated clinical outcomes. Topical treatments, including acyclovir cream, docosanol, and newer formulations, primarily reduce lesion duration and alleviate local symptoms when applied early. These interventions have limited systemic absorption and generally do not influence recurrence frequency. Novel delivery methods and combination strategies, such as acyclovir–hydrocortisone formulations or photodynamic therapy, may enhance local efficacy and symptom control. Systemic Therapies: Systemic antivirals, such as acyclovir, valacyclovir, and famciclovir, target both lesion resolution and recurrence prevention. Evidence from randomized trials supports their use for episodic and suppressive therapy, including short-course, high-dose regimens that improve adherence while controlling symptoms. Systemic therapy is particularly indicated for recurrent, disseminated, or high-risk infections. Topical and systemic therapies serve complementary roles in HSV management. Topical agents are useful for localized or initial episodes, while systemic therapy addresses broader clinical objectives, including recurrence reduction. Future research should focus on mechanism-based therapies, novel delivery systems, and standardized outcome measures to guide personalized treatment strategies. Emerging therapies targeting viral latency, immune modulation, and gene-editing technologies hold promise for long-term suppression and personalized management of HSV infections.
Mancini et al. (Mon,) studied this question.