Mixed methods are essential in public health research and malaria control, because they allow grasping part of the complexity and diversity of the factors that determine health-disease. This study analyzes the mixed studies on malaria in Colombia, 1980–2022, through a systematic review in 15 databases and institutional repositories. The methodological quality was assessed withMixed Methods Appraisal Tool(MMAT),STrengthening the Reporting of OBservational studies in Epidemiology(STROBE), andStandards for Reporting Qualitative Research(SRQR). The qualitative and quantitative findings were grouped into a four-level hierarchical matrix. The epidemiological profile of malaria morbidity, from traditional epidemiology, has been sustained by environmental problems, armed conflict, individual risk behaviors, and low adherence to recommendations from health institutions. However, the qualitative component reveals deeper causes that are less studied, of greater theoretical complexity, and that reflect challenges to design and implement health interventions, such as socioeconomic and political crises, poverty, and the neoliberal orientation in the malaria control policy; the latter reflected in the change in the role of the State, the fragmentation of control actions, the predominance of insurance over social assistance, the privatization of the provision of health services, the individualistic and economistic predominance of health, and low connection with popular tradition and community initiatives. The above confirms the importance of expanding mixed studies as a source of evidence to improve malaria research and control models in Colombia, and to identify the underlying causes of the epidemiological profile.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12889-023-16098-5.