The literature has demonstrated that teachers were susceptible to psychological issues such as anxiety, depression, and stress during the COVID-19 pandemic. However, there is a need to explore the underlying factors contributing to these psychological burdens. To investigate the independent and joint association of physical inactivity and excessive screen time with self-perceived health, quality of life, anxiety, and sadness among teachers working from home during the COVID-19 pandemic. This online cross-sectional study was conducted with 14,979 teachers from public schools in Minas Gerais, Brazil. Physical activity, TV viewing time, and computer/tablet use were self-reported. Health outcomes were assessed using a Likert scale. Adjusted logistic regression models examined the associations. Approximately 80% of the teachers were physically inactive (<150 min/week), while 10% and 80% spent more than 5 h/day watching TV and using a computer/tablet, respectively. Physical inactivity was associated with poor health, low quality of life, sadness, and anxiety. Excessive screen time was associated with low quality of life, sadness, and anxiety. Longer TV viewing time was associated with an increased frequency of sadness and anxiety. Interaction effects between physical inactivity and excessive screen time heightened the likelihood of adverse outcomes. Physical inactivity and excessive screen time independently contributed to the investigated health outcomes. The combination of physical inactivity and prolonged screen time increased the risk of poor self-perceived health among teachers during the pandemic.