Street nurses who serve people experiencing homelessness and substance abuse are at risk of vicarious trauma and long-term mental health challenges. These risks have increased during the COVID-19 pandemic due to a concomitant spike in opioid overdoses and deaths in Canada, fewer available support services and worsening social challenges. This article describes innovative interdisciplinary and participatory research currently being undertaken to develop and evaluate a multifaceted support program to promote the holistic well-being of street nurses and their front-line colleagues.