The purpose of the study was to assess the factors that affect students’ academic performance in Mathematics in Kakamega County. The study had five objectives: (i) Investigating the extent to which instructional methods contribute to the student’s performance in Mathematics at Secondary school level, (ii) find out the extent to which attitudes affect the performance in Mathematics in Kakamega County, (iii) assess the extent to which teachers experience affect study performance in Mathematics at secondary level in Kakamega County, (iv) find  out the extent to which teachers qualification affect  performance in Mathematics  in Secondary schools in Kakamega  County. (v) Investigate the extent to which physical and financial resources affect the performance in Mathematics in Kakamega County. The study was guided by Bruno’s theory of Knowledge and Organization. The study employed the Survey design. The survey design was selected for the study because it involves describing, recording, analyzing and reporting conditions as they are. The target population was 150 principals, 4,500 form four students, 60 teachers of mathematics and one QASO. This yielded a sample size of 15 schools based on the entry of boarding schools of each type of school. From each school, 1 Principal, 2 teachers of Mathematics and 45 students were sampled. Data was collected through a questionnaire, interview schedule for the county quality assurance and standards officer and observation schedule for the researcher.  The data was manually coded and descriptive statistics used for analysis. The statistical package  for social sciences SPSS, was used to analyze data and to determine  the correlation co-efficient of  each independent  variable  on the stepwise multiple regression analysis as well as  the  interactive  effect of  independent  variables. A pilot study was conducted to validate as appropriate the research instruments before the actual research commenced. The research used split-half method to determine the reliability of the research instruments which scored, r = 0.78. Qualitative and quantitative data was collected and the findings were presented by use of descriptive narrative, frequencies and percentages. The study established that there was a strong positive relationship between the teachers level of classroom preparedness, practice and instructional methods which influence the students’ academic performance in Mathematics. The study further established that personal character, attitudes of students towards Mathematics was strongly affected by fellow students’ perception of the subject. The study established that teacher’s experience affect the academic performance in Mathematics to a great extent. Student-textbook ratio and student-teacher ratio did not directly influence student performance in Mathematics. From the findings, the study concluded that teachers rarely incorporated varied learning activities in Mathematics lessons, their teaching methods and strategies were ineffective and inefficient. To enhance the incorporation of learning activities during Mathematics instructions, the study recommended reduction of Mathematics teacher workload to afford them adequate time to prepare and deliver the content effectively and efficiently. There is need for mounting of more regular in service training and education on pedalogy and attitude change in Mathematics by both students and teachers. For performance in mathematics to improve in secondary schools in the County, the study recommended that the government and other educational stakeholders should provide secondary schools in the county with sufficient capital, learning materials and human resources which should be equitably distributed in good time, based on each school population of students to avoid learning and teaching disruptions.