•The prevalence of Herpes continues to increase in spite of existing programs and hence, improved public health efforts are urgently needed.•Both, mild (constitutional) or severely (nonconstitutional) infected contribute to the transmission and so, both needs consideration.•Current treatment strategies only target individuals at the nonconstitutional stage, and miss mild cases, which are hard to detect and treat.•The proposed strategy of this study consists of treating patients in both stages and resulted in reduction of the incidence of Herpes by 38%.•The proposed strategy cost less and decreases R0 by 40% and hence, it has much higher potential for eliminating disease. Infection of Herpes Simplex Virus type 2 (HSV–2) is a lifelong sexually transmitted disease. According to the Center for Disease Control and Prevention (CDC), 11.9% of the United States (U.S.) population was infected with HSV–2 in 2015–2016. The HSV–2 pathogen establishes latent infections in neural cells and can reactivate causing lesions later in life, a strategy that increases pathogenicity and allows the virus to evade the immune system. HSV–2 infections are currently treated by Acyclovir only in the non-constitutional stage, marked by genital skin lesions and ulcers. However, patients in the constitutional stage expressing mild and common (with other diseases) symptoms, such as fever, itching and painful urination, remain difficult to detect and are untreated. In this study, we develop and analyze a mathematical model to study the transmission and control of HSV–2 among the U.S. population between the ages of 15–49 when there are options to treat individuals in different stages of their pathogenicity. In particular, the goals of this work are to study the effect on HSV–2 transmission dynamics and to evaluate and compare the cost-effectiveness of treating HSV–2 infections in both constitutional and non-constitutional stages (new strategy) against the current conventional treatment protocol for treating patients in the non-constitutional stage (current strategy). Our results distinguish model parameter regimes where each of the two treatment strategies can optimize the available resources and consequently gives the long-term reduced cost associated with each treatment and incidence. Moreover, we estimated that the public health cost of HSV–2 with the proposed most cost-effective treatment strategy would increase by approximately 1.63% in 4 years of implementation. However, in the same duration, early treatment via the new strategy will reduce HSV–2 incidence by 42.76% yearly and the reproduction number will decrease to 0.84 from its current estimate of 2.5. Thus, the proposed new strategy will be significantly cost-effective in controlling the transmission of HSV–2 if the strategy is properly implemented.