Herpes Simplex Virus (HSV) types 1 and 2 are significant etiologies to central nervous system (CNS) infections, leading to potential severe neurological consequences. Despite their global impact, our region’s data on the epidemiology of HSV CNS infections remains limited. This study assessed the epidemiology and diagnostic trends of HSV-1 and HSV-2 CNS infections in a tertiary hospital in Southwestern Saudi Arabia from 2018 to 2023. A retrospective study was conducted using data from cerebrospinal fluid (CSF) samples collected from patients with suspected CNS infection between 2018 and 2023. Polymerase Chain Reaction (PCR) results for detecting HSV-1 and HSV-2, performed as part of routine clinical diagnostics, were analyzed. Data on patient demographics, specimen collection times (including months and years), laboratory processing times, and seasonal trends were collected and analyzed using descriptive statistics and univariate analysis. Of the 280 samples, 11.0% were positive for HSV, with 10.0% positive for HSV-1 and 1.0% for HSV-2. Most HSV-positive cases were found in patients aged ≥51 years (27.0%). Peak detection occurred in 2020, with seasonal spikes in May and September. The turnaround time significantly varied, with the shortest laboratory turnaround time for PCR results recorded in 2020 (35.54 hours), while the longest was in 2021 (167.38 hours). This study reports an important burden of HSV-related CNS infections in Southwestern Saudi Arabia, indicating the importance of timely diagnosis through PCR testing. Our findings highlight the need for improved diagnostic workflows and enhanced epidemiological surveillance. Future research should explore broader regional and clinical data related to HSV CNS infection epidemiology.