This study investigated the factors that contribute to the non-science students’ lack of interest in school science through the use of a 27-item questionnaire. This assisted in comparing the male and female non-science students’ lack of interest in school science. There were 259 male and female students from three senior high schools in three District Assemblies of the Ashanti Region of Ghana who participated in the study. Quantitative data were collected from the 259 students through a cross-sectional survey. The research questions were answered with mean, standard deviation, percentage, boxplot, and independent-samples t-test. The results of the study have shown that the factors that contribute to students’ lack of interest in school science include as higher demands of students’ time in learning science, less practical nature of science teaching and learning, failure of science students with larger aggregate from high school to gain admission into tertiary institutions, too broad nature of science content, lack of sponsorship for science students, school science as difficult subject compared to others, and teaching of science is a transmission of knowledge from science teachers or textbooks to students. The results of the study have further shown that there was a statistical significant difference between the mean scores of male and female non-science students’ lack of interest in school science. Science teachers are therefore encouraged to adopt strategies that could encourage students to develop and show interest in science related subjects and courses.