One approach for understanding teachers’ behavioral responses to classroom student misbehavior is through the perceptions of efficacy in handling this stressor. The present study investigated the relationship and predictive ability of personal and school cultural factors as they relate to perceptions of teachers’ efficacy in handling student misbehavior (TEHSM). Participants were 344 primary (n = 189) and secondary (n = 155), full-time, public school teachers from a southeastern state in the USA. Teachers completed online self-report measures of TEHSM and all personal and school cultural factors. Student socioeconomic status (SES) information was provided by the school districts. Structure equation modeling (SEM) results indicated the final empirical model to account for 66% of the variance in TESHM, with professional development and student SES having the strongest association with TEHSM. This study provides a vital step towards understanding factors that drive teachers’ perceptions of their efficacy in handling misbehaving students.