: Acyclovir is an antiviral drug frequently used in clinical practice. It is indicated for the treatment of infections caused by herpes simplex virus and varicella zoster virus. The drug has a good safety profile; however, severe side effects may rarely occur during therapy. These include renal failure as a major risk factor for neurotoxic side effects potentially developing within 24-48 hours of therapy initiation. The paper presents the cases of two patients developing neurotoxic side effects while treated for herpes zoster. The aim of the authors is to highlight the potential for developing neurotoxic side effects in high-risk groups such as the elderly, patients with impaired renal function or multiple comorbidities on polypharmacy, or those using nephrotoxic drugs. Acyclovir use could lead to renal impairment and an increase in its plasma and CNS concentrations with severe neuropsychiatric side effects. The neurotoxic side effects are reversible after therapy withdrawal. Thus, in patients developing mental impairment or showing other neurological symptoms during acyclovir therapy, the patient should be promptly assessed for potential drug neurotoxicity, their therapy should be discontinued and drug elimination with forced diuresis or hemodialysis considered. Early recognition of acyclovir neurotoxic side effects can significantly improve a patient's prognosis.