Even a cursory review of the research literature over the past two decades will reveal many e-learning implementation challenges facing sub-Saharan Africa Higher Education Institutions. The last available systematic review of these challenges was conducted in 2017. To address this gap and by following the PRISMA-ScR guidelines, our systematic review aimed to find answers to the following two research questions: (a) What e-learning challenges were identified in research conducted in Higher Education Institutions in sub-Saharan Africa from 2016, and (b) Which e-learning challenges identified before 2016 remain and which are new? Using search terms and synonyms associated with e-learning challenges, three reviewers performed a Boolean search in Google Scholar, Web of Science, and Scopus. After duplicates (113) were removed, a total of 353 potential articles were imported into a collaboration platform and filtered using the following inclusion criteria: (1) Higher Education Institutions in sub-Saharan Africa (2) English articles from 2016 to 2022 (3) user data on real-world e-learning implementations are available (4) use of a computer/mobile device excluding m-learning approaches and (5) blended or fully online courses. After a selection process where article sets were reviewed, rotated, and conflicts resolved, 25 articles that met the inclusion criteria formed the primary evidence base. After a data collection process and using selected Grounded Theory techniques, a total of 48 challenges, synthesised in 25 challenge categories, were identified across six themes: university-related (36 citations), instructor-related (20), access-related (14), LMS-related (10), student-related (9) and computer literacy-related (9). The main challenges categories were ICT infrastructure (14 citations), technical support (10) and student bandwidth (8), while the secondary challenges were mainly related to the instructor: commitment and capacity (7), capacity (6), LMS training (6) and instructional design and support (5). Suggestions are offered to address key challenges related to ICT infrastructure, technical support, and student bandwidth. Secondary challenges, which are mainly related to the instructor, are proposed to be resolved by a skilled and energetic instructional design and support team. Although many challenges identified before 2016 were reinforced in this investigation, no new challenges were identified. Overall, the number of citations for specific challenges shows that most challenges are context-specific, that is, limited to single HEIs. However, when combined in challenge categories and reflected as themes, the review reveals many challenges to remain persistent. To ensure that an institution, its instructors, and its students are geared and supported stepwise, a holistic top-down approach that considers all challenges is required. To achieve this, a recommendation for further research is the development of an updated SSA-specific checklist that can be used to rate e-learning readiness in terms of importance and context. The research aims to provide active researchers in the field with an update on the status of research on e-learning challenges in SSA, as well as to make decision-makers aware of potential challenges when implementing e-learning in the SSA context. This may result in better institutional strategies to support e-learning practitioners, as well as to ensure the effective development and implementation of e-learning management systems.