Globally, health literacy (HL) is a critical component in the promotion of health and well-being. Like in many other places in the world, improving HL in low- and middle-income countries (LMICs) is essential for achieving better health outcomes and requires a multifaceted approach that considers the local context. It is through construction of accessible and actionable knowledge that LMICs can empower their populations toward informed health decisions, hence improvement of quality of life. Health literacy and knowledge construction in health-related matters have always been inextricably linked. Apparently, health-related knowledge is associated with HL much as HL seems to influence health knowledge. This chapter analyzes the state of the art on HL and knowledge construction in LMICs. It specifically discusses the initiatives on creation of health-related knowledge hence enhancement of HL and vice versa. Furthermore, the chapter analyzes how accessible and actionable knowledge has been constructed to empower people toward making informed health decisions, hence attaining optimal health consequently improving quality of life in LMICs. In this chapter, innumerable challenges are also discussed. Notably most of LMICs have been observed to stand behind with respect to investing in both construction of knowledge on health but also on HL initiatives. In most of the LMICs, very little investment has been made in documenting and researching on this important aspect. Major national health data sets are lacking in these countries, and some do not even mention this important aspect. It is concluded that there is knowledge gap on both HL and construction of health-related knowledge which depend on each other. Incognizant of this, it is recommended that the governments in the LMICs should further invest in these important aspects toward attainment of optimal health for the population.