The COVID-19 pandemic and related school disruptions have led to increased concerns for the mental health of teachers. This study investigated how the challenges and systemic supports perceived by teachers during the COVID-19 pandemic were associated with their mental health and workplace well-being. This cross-sectional, survey-based study was conducted in February 2021, just prior to the third wave of the pandemic in British Columbia (BC), Canada (N = 1,276). Four multivariable linear regression models examined the associations between teachers’ pandemic-related challenges (pandemic-related personal stressors, teacher workload, difficulty implementing safety measures, meeting students’ needs), systemic supports (education system mental health and well-being support), and four mental health (psychological distress, and quality of life) and workplace well-being outcomes (job-related positive affect, turnover intentions), adjusting for sociodemographic and school characteristics. The Pratt index (d) was used to assess the relative importance of each predictor. A thematic qualitative analysis was conducted on teachers’ open-ended responses. Teachers’ workplace well-being (job-related positive affect and turnover intentions) was predominantly associated with their perceptions of education system support for their mental health and well-being (d = 46%, d = 41%, respectively). The most important predictor of general mental health (psychological distress and quality of life) was the number of COVID-19 related personal stressors teachers reported (d = 64%, d = 43%, respectively). The qualitative analyses corroborated and expanded upon the quantitative findings. Understanding pandemic-related challenges and supports impacting teacher mental health and workplace well-being equips us to make evidence-informed policy decisions to support teachers now and in future school disruptions.