This study sought to examine the relationships among mathematics self-efficacy, mathematics teaching self-efficacy, mathematics anxiety, and instructional practices of senior high school mathematics teachers in the Ashanti Region of Ghana, while assessing the moderating role of school climate. Using validated scales to collect data from 443 teachers and analyzing the data using partial least squares structural equation modelling, the results showed that mathematics self-efficacy and mathematics teaching self-efficacy significantly improved mathematics teachers’ instructional practices. Though mathematics anxiety had a negative effect on instructional practices, the effect was found not to be statistically significant. The results further indicated that school climate and mathematics self-efficacy are significant predictors of mathematics teaching self-efficacy. Additionally, school climate was found not to significantly strengthen or weaken the relationship between mathematics self-efficacy and instructional practices, or the relationship between mathematics anxiety and instructional practices. Also, the results showed that the relationship between mathematics self-efficacy and mathematics teaching self-efficacy was not strengthened by school climate. These findings highlight that teachers’ efficacy beliefs are the most consistent drivers of instructional practices, while school climate indirectly contributes by strengthening teaching self-efficacy. The implications for practice are that professional development initiatives should prioritize building mathematics teachers’ self-efficacy, as this is directly linked to improved instructional effectiveness. Additionally, fostering a supportive school climate can reinforce teaching self-efficacy, thereby indirectly enhancing instructional practices. While reducing anxiety remains important for teacher well-being, it may not independently influence classroom practices unless combined with efficacy-building and climate-support strategies. This evidence underscores the central role of efficacy beliefs, supported by positive school environments, in shaping effective mathematics instruction in Ghanaian senior high schools.