As the pandemic began, university instructors shifted their classes online to ensure learning for numerous students. While teaching online, the instructors soon encountered many challenges. Existing studies have explored different kinds of challenges through surveys or interviews with instructors. However, to our knowledge, no studies have reported instructors’ challenges in online teaching during COVID-19 through a systematic literature review. Moreover, there are no studies that have suggested design guidelines for creating tools to help instructors. Thus, we identified various challenges that university instructors face while teaching classes online, along with the causes of the challenges, through conducting a systematic review using the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines. Only the studies (a) reporting the challenges of instructors in online teaching, (b) having reported challenges regarding online teaching during COVID-19, and (c) reporting challenges of instructors from universities/colleges were considered in the systematic review. We found that the biggest category of the challenges that university instructors faced was managing/conducting online classes. Lastly, we propose design opportunities to help instructors to teach an online class more effectively and in interactive ways. This review shows the possibility of overcoming the existing challenges in online teaching with instructors receiving the appropriate support and tools for online classes. Additionally, we suggest some recommendations for future research. We hope this review contributes to a deeper understanding of university instructors’ struggle in online classes and suggests potential solutions for supporting instructors in online education.