Background: The WHO African region frequently experiences outbreaks and epidemics of infectious diseases often exacerbated by weak health systems and infrastructure, late detection, and ineffective outbreak response. To address this, the WHO Regional Office for Africa developed and began implementing the Integrated Disease Surveillance and Response strategy in 1998. Objectives: This systematic review aims to document the identified successes and challenges surrounding the implementation of IDSR in the region available in published literature to highlight areas for prioritization, further research, and to inform further strengthening of IDSR implementation. Methods: A systematic review of peer-reviewed literature published in English and French from 1 July 2012 to 13 November 2019 was conducted using PubMed and Web of Science. Included articles focused on the WHO African region and discussed the use of IDSR strategies and implementation, assessment of IDSR strategies, or surveillance of diseases covered in the IDSR framework. Data were analyzed descriptively using Microsoft Excel and Tableau Desktop 2019. Results: The number of peer-reviewed articles discussing IDSR remained low, with 47 included articles focused on 17 countries and regional level systems. Most commonly discussed topics were data reporting (n = 39) and challenges with IDSR implementation (n = 38). Barriers to effective implementation were identified across all IDSR core and support functions assessed in this review: priority disease detection; data reporting, management, and analysis; information dissemination; laboratory functionality; and staff training. Successful implementation was noted where existing surveillance systems and infrastructure were utilized and streamlined with efforts to increase access to healthcare. Conclusions and implications of findings: These findings highlighted areas where IDSR is performing well and where implementation remains weak. While challenges related to IDSR implementation since the first edition of the technical guidelines were released are not novel, adequately addressing them requires sustained investments in stronger national public health capabilities, infrastructure, and surveillance processes.