Water security is critical to the health and well-being of people around the world, especially among populations experiencing water stresses and rapid urbanization in low- to middle-income countries (LMICs). Recent research suggests water insecurity is associated with negative mental health outcomes. Despite global improvement in access to safe water across the world, the World Health Organization (WHO) reports that access to safe water in urban areas has not changed significantly or has stagnated in certain countries. In most African cities, entrepreneurial water vendors have stepped up to fill supply gaps in the formal delivery system by selling vended water. As part of a larger research program that aims to assess and analyze public perceptions around vended water, this paper explores the links connecting water insecurity and emotional distress among urban slum dwellers who mostly use vended water in Accra, Ghana. We used a parallel mixed-methods approach. Our quantitative results show that water-insecure households (OR = 2.23, = 0.01) were more likely to report emotional distresses compared to water-secure households. However, households with improved sanitation (OR = 0.28, = 0.01) and those willing to participate for improved water and sanitation (OR = 0.28, = 0.01) were less likely to report emotional distress. Our qualitative results offered support for the quantitative results, as participants not only hold various perceptions regarding the safety and quality of vended water but expressed emotional distresses such as fear of contamination, discomfort, worry over arbitrary change in prices, and anxiety. The implications of the results for policy and practice, specifically to ensuring access to safe water, are discussed.