While evidence exists for effective remote mindfulness-based interventions (MBI) with nurses, and during the COVID-19 pandemic, less literature exists supporting effectiveness in broader groups of healthcare workers (HCWs). A clinically validated MBI was evaluated in HCWs at an academic medical center during COVID-19. Remote 1.5-h, 6-week sessions met throughout 2021–2022. Sessions included social support, educational, and mindfulness components. Pre-post analyses (n = 52) evaluated anxiety, depression, burnout, self-rated general health, and Self-Compassion at baseline (Week 1), program conclusion (Week 6) and 3-months post-intervention using mixed effect linear regression models. Program acceptability was measured at Week 6 with a single-item question ranking usefulness across all six sessions. Anxiety (−3.4 [95% CI −4.9, −1.9]), depression (−6.2 [95% CI −8.7, −3.7]), and burnout (−0.33 [95% CI −0.6, −0.11]) were significantly reduced from Week 1 to Week 6. Reductions were maintained 3-months post-intervention. Self-Compassion significantly increased (0.3 [95% CI 0.2, 0.5]) from Week 1 to Week 6, and this increase was maintained 3-months post-intervention. There was no significant change in self-rated general health. All sessions were acceptable. These results support the implementation of remote MBI for HCWs given continued mental health burdens in this workforce.