This paper investigated the interactive effects of gender and cognitive ability levels on students' academic performance of Biochemistry students in six federal universities located in South-south, Nigeria using glucose metabolism as a case subject. A research question, an objective and a hypothesis wer formulated to guide this study. Quasi-experimental research design was adopted which used the pre-test-post-test non- randomized control group. The study sample consisted of two hundred (200) Year 2 Biochemistry students in four intact classes of four randomly selected federal universities in South-south, Nigeria, during the 2019/2020 academic session. Performance Test on Glucose Metabolism (PTGM) with reliability indices of .75 was developed by and used for relevant data collection. PowerPoint Instructional Package on Glucose Metabolism (PIPGM) was applied for the treatment group classroom teaching while students in the control group were taught the same concept using expository method. At the end, the Performance Test on Glucose Metabolism (PTGM) used as pre-test was reshuffled and re-administered as post-test. The research question was answered using mean performance scores of students on the concept of Glucose Metabolism in Biochemistry when taught using PowerPoint instructional media and without PowerPoint. The hypothesis was tested using Analysis of Covariance (ANCOVA) with post-test scores as covariates. Findings revealed that, except for the case of treatment - cognitive ability levels interactions, the effects of treatment on students' academic performance were the same at all levels of gender and cognitive ability levels. This also underscored the effectiveness of PowerPoint instructional strategy in facilitating students' academic performance while at the same time indicating that neither gender nor students' cognitive ability levels is a strong determinant of students' academic performance in the concept area. The recommendation therefore follows that the discrimination on gender basis should be discouraged while the continuous use of instructional tools be encouraged thereby impacting the success expectancy of learners.