Herpes simplex virus type 1 (HSV-1) remains a widespread human pathogen responsible for recurrent infections and significant health burdens. The emergence of drug resistance and limitations of existing antiviral therapies highlight the need for the development of novel antiviral agents with improved efficacy and safety profiles In this study, a library of novel 1,2,4-triazole derivatives fused with a pyrazine moiety (5a–5t) was successfully synthesized and evaluated for their therapeutic potential against HSV-1 and oxidative stress. These compounds were assessed for anti-inflammatory, antioxidant, and anti-HSV–1 activities, demonstrating encouraging biological profiles. In particular, compounds 5f and 5t exhibited markedly improved antiviral efficacy compared to the reference drug, acyclovir. The antioxidant capacity was also notable, with compound 5b showing exceptional radical scavenging potential. Docking studies were conducted to better understand their molecular interactions with the target protein. The findings demonstrated that these molecules could potentially inhibit HSV-1, targeting a key enzyme involved in viral replication. Additionally, in silico analyses were performed to assess drug-likeness, absorption, distribution, metabolism, and excretion characteristics, and metabolic stability, which may aid in the optimization of future lead compounds. Although the experimental methods were accurately implemented, minor variations associated with human error, such as differences in timing during compound administration, measurements, and other experimental procedures, may have occurred. These possible variations, however, are unlikely to significantly affect the observed trends. Ultimately, the study emphasizes these new triazole–pyrazine hybrids as potential lead compounds for the development of potent anti-HSV–1 and possibly antibacterial agents, warranting further pharmacological and clinical investigation.