Background: To be successful, students must learn to deal with socially and cognitively demanding tasks. Much remains unknown about the effects of previous classroom experiences and of students' emotional appraisal of a task on their physiological adaptive responses to it. Aims: To investigate how children's physiological response to a social and cognitive task would be directly and interactively influenced by the perceived student-teacher relationship and by children's emotional appraisal of what reaction they expect to have while completing the task. Methods: One hundred and sixteen second and third graders took part in the study. Children completed a cognitive and social stress task. Before the task, they were interviewed on their emotional appraisal of the task and on student-teacher relationships. Children's cardiac activity was registered at rest and during the task to measure physiological activation (heart rate) and self-regulation (heart rate variability). Results: Heart rate variability during the task was positively correlated with the appraised emotional valence of the task and of being observed while doing it. Regression analyses showed that children's physiological self-regulation during the task was affected by the interaction between student-teacher relationships and appraised emotional valence of being observed. Only among children who had experienced negative student-teacher relationships, an active physiological self-regulation was observed in response to the task when they expected it to be positive compared to when they perceived it as negative. Conclusions: Children's emotional appraisal of tasks and the quality of student-teacher relationships are important to promote a functional physiological response of self-regulation that underlies academic functioning and well-being at school.