Understanding factors associated with health literacy remains important in scaling up health literacy initiatives towards attainment of good health. This article discusses health literacy and associated factors under One Health Approach from a cross sectional study in selected wards in Eastern Tanzania. A structured questionnaire was used to collect data from 1440 respondents obtained through multistage sampling procedure. Health Literacy assessment tool was developed to assess health literacy. IBM-SPSS v.20 analyzed quantitative data while qualitative data were organized into themes on specific objectives to back up findings. Multiple regression was employed to explore the correlation or relationship between health literacy (HL) and numerous continuous independent variables. The study revealed that HL score had a large correlation with HB r = -.631, p= .000, N= 1440), LGAs r = .617, p= 000, N=1440, Influence of politics scorer = .082, p= .001, N=1440; Prior knowledge score r =-.082, .001, N=1440; Scores on HRDE r =.347, .000, N=1440; Score on EoHRA r =.099, .000, N=1440; Years spent on studies r =.125, .000 and Attitudes towards HIB r =-.082, .001, N=1440. The strongest unique contribution associated to HL was found from Health Behaviour Score with beta coefficient of -.474, while Local Government Authorities initiatives on health (.294), Influence of politics on health score (.249), interactions with professionals score (.078), and scores on Health Related Discussion Engagement (HRDE) (.151) are making statistically significant unique contribution to the model in terms of prediction of HL. It can be noted that there are various factors that are associated/correlating with HL with differing magnitude but some having no unique contribution to the variable. Effective HL interventions towards attainment of good health has to take on board the extent to which such associated factors are likely to make contribution to HL hence capitalizing on such contributions.