Teaching is a challenging profession, and teachers experience stress due to the difficulties associated with shifting educational policies, disengaged or dissatisfied parents, and the behavioral, emotional, and academic needs of diverse students. This stress can lead to burnout, which often results in departure from K-12 education system. These stressors can also reduce teachers’ sense of self-efficacy, i.e., their perceived ability to accomplish tasks and overcome challenges. These elevated levels of stress and burnout and reductions in self-efficacy negatively impact student outcomes. In this study, we evaluated the potential for cooperative learning (CL) to reduce stress and burnout and enhance teacher self-efficacy. To aid in the implementation of CL and reduce the burden on teachers, we used an innovative software platform (PeerLearning.net). Data were from a cluster randomized trial encompassing 12 middle and high schools (N = 111 teachers, 62.2 % female, 86.5 % White). We found that teachers in intervention schools (i.e., schools given training and access to PeerLearning.net) reported reduced levels of stress and beneficial effects on self-efficacy (i.e., higher levels of Student Engagement and Instructional Strategies) and burnout (i.e., reductions in Emotional Exhaustion and higher levels of Personal Accomplishment) compared to teachers in control schools that conducted business as usual. We found no significant differences in Classroom Management (an element of self-efficacy) and Depersonalization (an element of burnout). These results suggest that CL, implemented with PeerLearning.net, can have some beneficial effects on teacher well-being.