AIMS: This study aims to investigate the safety profile of Esketamine, with a particular focus on comparing adverse events (AEs) between adults (< 65 years) and older adults (≥ 65 years) using data from the FDA Adverse Event Reporting System (FAERS). METHODS: We conducted a comprehensive analysis of FAERS data from 2019 to 2024, identifying 6,452 Esketamine-related AE reports. After removing data without age information, these reports were categorized into two age groups: 536 from older adults and 3,566 from younger adults. Reporting odds ratios (RORs) were calculated to determine the relative risk of specific AEs in each age group. RESULTS: At system Organ Class (SOC)level, the Esketamine-related AEs of both adults group and older adults group were seen in 17 organ systems. The analysis revealed significant differences in AE profiles of psychiatric disorders between the two age groups. Older adults had a higher incidence of dissociation, suicidal ideation, depression, and anxiety, compared to younger adults. Additionally, older adults reported more general and administration site conditions, suggesting a greater susceptibility to systemic and local reactions. Gastrointestinal and respiratory disorders were less frequent in older adults, but their potential impact remains critical. CONCLUSIONS: The findings highlight a higher risk of severe psychiatric and general AEs in older adults treated with Esketamine, necessitating careful patient selection, monitoring, and tailored treatment protocols.