Because of its hydrophilicity, acyclovir is an antiviral medication with a low oral bioavailability of about 20% and is poorly absorbed in the gastrointestinal tract. Herpes simplex encephalitis (HSE) is treated with acyclovir; nonetheless, the disease has a terrible prognosis, especially if therapy is delayed, with fatality rates as high as 70% if treatment is not received. Therefore, in adults with normal renal function, substantial doses of acyclovir are given via intravenous (IV) infusion, often at a dosage of 10 mg kg−1 8 hourly. Nonetheless, the death rate associated with HSE treated with acyclovir is still high (~20%), and reports of long term effects (~50%) are typical after a year. Novel discoveries that attempt to improve drug bioavailability—such as acyclovir or its prodrugs—were evaluated. This could result in the medicine being targeted for systemic distribution. Much research has been done to enhance antiviral therapy. Specifically, efforts have been made to find delivery systems that can increase the bioavailability of acyclovir using non-invasive pathways like the nasal and oral pathways, or through parenterally delivered nanotechnology-based systems that can target specific drugs. Nanocarriers, albeit not yet produced on an industrial scale, are viable solutions for treating HSE when supplied through non-invasive channels.