This study has been an attempt to determine factors influencing the teaching-learning process of Mathematics in some selected general secondary schools of Enemay Woreda (district) in Amhara region. The objectives of this research were to find out the major existing factors that influence the teaching-learning of Mathematics in some selected general secondary schools of Enemay woreda in Amhara region and to establish the strategies and propose possible solutions that can be adopted to improve the situation. Regarding methodology of the research a mixed research approach (triangulation) was used to collect data from teachers, schools’ principals, department heads and students involved in the teaching and learning of Mathematics. A sample of 200 students were selected by using simple random sampling; 26 Mathematics teachers, 3 schools’ principals and department heads were selected by using purposive sampling techniques. Regarding data gathering instruments semi-structured interview, questionnaires with closed-ended questions and observation were used to gather both qualitative and quantitative data. Information was analyzed quantitatively and qualitatively. In relation to the basic findings of this research it was found that the problems of the teaching-learning of Mathematics are multi-faceted and accordingly the solutions require overall effort from all concerned stakeholders. The factors could be grouped into different categories such as teacher related, student related, curriculum related, learning environment related, instructional material and other resources related, language related factors. I believe this study will have its own contribution in the effort of identifying some of the major aspects which obstruct the teaching and learning of Mathematics and thereby towards possible solution. It could be also used as an initial work for those who are interested to carry out further studies in this issue.