Tobacco use is the world’s leading preventable cause of illness and death and the most important risk factor for non-communicable diseases (NCDs), particularly cardiovascular and chronic respiratory diseases (heart attack, stroke, congestive obstructive pulmonary disease and lung cancer). A Multi-Sectoral Approach (MSA) in the context of health refers to actions of sectors outside the health sector, possibly, but not necessarily, in collaboration with the health sector, on health or health-related outcomes or the determinants of health or health equity. The operational definition of evidence of MSA in this study is “involvement of any two or more sectors, one of which must be government”. Engaging in multi-sectoral actions is done using three primary approaches: inter-sectoral action, healthy public policy and health in all policies. This study assessed NCDs prevention policies related to the WHO recommended “best-buy” interventions for NCDs prevention, in South Africa and in Togo, and investigated the use of MSA in the formulation and implementation of tobacco control policies. To address the five study objectives, the study generated data from a documentary review on NCDs prevention policies and interviewed 56 key informants in both countries (26 in South Africa and 30 in Togo) on the formulation and implementation of tobacco control policies. The study used mixed methods and developed a “Comprehensive Framework for Multi-Sectoral Approach to Health Policy” to analyse study data. The framework is built around four major constructs of context, content, stakeholders and strategies. Study results indicate policies addressing the major risk factors of NCDs namely tobacco use, harmful use of alcohol, unhealthy diet and physical inactivity have been formulated and implemented in South Africa and in Togo, with all four risk factors addressed in South Africa and only 3 in Togo, where unhealthy diet is yet to be addressed. Further, there was evidence of use of MSA in policy making process although more in formulation than implementation. Both countries ratified the WHO Framework Convention on Tobacco Control (FCTC) in 2005 and since then substantial efforts were made to pass comprehensive legislations on tobacco control, though these laws are not yet fully WHO FCTC compliant. The stakeholders involved in tobacco control policy formulation were more diverse, proactive and dynamic in South Africa than in Togo whereas the strategies employed were more straightforward in Togo than in South Africa. The extent of understanding and use of MSA in both countries consisted of an inter-sectoral action for health whereby the health department strived to collaborate with other sectors within and outside the government. Consequently, information sharing was identified as the main outcome of the interactions between institutions and interest groups within and across three critical sectors of the state, namely: the public (government), private and civil society. This resulted in sub-optimal implementation of tobacco control policies in both countries. In South Africa, local expertise through several scientific publications from research and academic institutions and a strong political will initially from the post-apartheid government were the most important facilitating factors both at the policy formulation and implementation stages, and they were higher than the ratification of the WHO FCTC. Conversely, in Togo, the WHO FCTC was the leading facilitator of the use of MSA in tobacco control policy making process. In both countries, the tobacco industries have been the main barriers to the formulation and implementation of tobacco control policies, but they are stronger in SA than in Togo because of their reported contribution to country revenues and their ties with the ruling power, particularly during the apartheid era. In reference to the three approaches to engaging in MSA mentioned above, inter-sectoral action is at the beginning of a continuum of degrees of policy integration. Therefore, to improve the inter-sectoral understanding and use of MSA on tobacco control policies in SA and Togo, this study recommend to move from an inter-sectoral action for health led by the Health Department to a multi-sectoral approach-whole of government-to health, managed by a national multi-sectoral mechanism at the cabinet level, which will ultimately improve policy coherence across government and yield significant progress toward sound formulation and implementation of comprehensive tobacco control policies.