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The study examined the mediating roles of students' perception of mathematics, students' self-efficacy and cooperative learning strategies in the relationship between teacher-student relationship and students' mathematics achievement in all the senior high schools at Atwima Nwabiagya North District. The study was carried out using the descriptive survey design. The target population was second-year students. Through purposive, proportionate stratified, and simple random sampling techniques, questionnaires were administered to 346 second year students, however, 320 questionnaires were returned. The data collected were analyzed using structural equation model with bootstrap samples. It was found that teacher-student relationship was significant negative predictor of students' mathematics achievement. The study also discovered that, students' perception of mathematics, students' self-efficacy and cooperative learning strategies were partially mediated the relationship between teacher-student relationship and students' mathematics achievement. It was suggested based on the findings that mathematics teachers should be mindful of their relationship with the students, employ varieties of techniques when dealing with students with bad perception of mathematics and also consider the kind of collaborative learning techniques to be adopted in order to accelerate students' mathematics achievement.