BACKGROUND: A knowledge gap exists in understanding the role of social isolation as a determinant of mental health among hybrid employees during the COVID-19 era. METHODS: Using 2024 Household Pulse Survey data, we investigated the relationship between social isolation and mental health among US hybrid employees. We assessed depression symptoms using the Patient Health Questionnaire-2 and anxiety symptoms using the Generalized Anxiety Disorder-2. Social isolation was assessed using five items adapted from the Berkman-Syme Social Network Index. Covariates included age, race/ethnicity, gender identity, educational attainment, employment sector, household income, marital status, number of children, number of remote workdays, and region. Weighted multivariable logistic regression models estimated the adjusted associations between social isolation and mental health. RESULTS: Compared to those in the less than once a week group, those who had a phone call with family, friends, or neighbors at frequencies of 1-2, 3-4, or 5+ times per week were significantly less likely to experience depression and anxiety symptoms. We observed similar statistically significant patterns when modeling each mental health outcome with weekly frequencies of social gatherings with friends or relatives, annual frequencies of church or religious service attendance, and annual frequencies of club or organization meeting attendance. LIMITATIONS: Observed associations do not establish causality. CONCLUSIONS: More frequent interpersonal communication, social gatherings, and attendance at organization meetings were significantly associated with better mental health. This empirical evidence provides meaningful insights for stakeholders, such as employers, human resources departments, psychiatrists, and hybrid employees.