This paper seeks to establish whether there is a statistically significant difference in students’ academic performance in mathematics and non-mathematics courses using face-to-face, online, and blended instruction. The study is quantitative research and employs a case study approach covering 603 students at the Catholic University of Ghana. The paired sampled t-test is adopted to analyze the data set. The study found that at a 5 percent significant level, there is no statistically significant difference in students’ academic performance in mathematics and non-mathematics courses using face-to-face instruction. Conversely, a statistically significant difference exists in students’ academic performance in mathematics and non-mathematics courses using online and blended instructions. The study concludes that non-mathematics courses can be best taught using online instruction whereas mathematics-related courses can best be taught using blended instruction. However, face-to-face instruction leads to no difference in students’ academic performance.