The District Health Information Systems 2 (DHIS2) has been implemented in many countries as a standard tool for managing health information for decision making. Despite the continued adoption of this system in developing countries, some challenges affecting its effective use still exist. Previous studies have indicated that the majority of these challenges are mainly infrastructural and system related. As ICT infrastructure continues to improve, the need to investigate challenges affecting DHIS2 usage beyond infrastructural and system factors is important. In this study, factors influencing DHIS2 usage in Sierra Leone were investigated using the Technology-Organization-Environment (TOE) framework. Mixed sequential explanatory design was adopted using data from 126 respondents in 10 districts followed by focus group discussions. The study found that top management support, perceived benefits, security and privacy, and compatibility were significant predictors of DHIS2 usage in Sierra Leone. Similarly, poor Internet connectivity, lack of security policies and guidelines, and shortage of qualified staff were identified as challenges affecting the effective use of DHIS2. Recommendations for helping the Ministry of Health and Sanitation in Sierra Leone and other donors to ensure that DHIS2 is effectively used are discussed.