Background: Comprehensive tool is not available to assess health literacy status across different languages, contexts and population structures except European health literacy survey scale (HLS-EU-Q47) which is widely used adapted and tested in different countries and languages. However, it was not tested for Ethiopian populations. This study aim was to validate and test the reliability of the Amharic version of the HLS-EU-Q47 survey questionnaire (HLS-Amh) among school adolescents and university students in Dire Dawa, Ethiopia. Method: A cross-sectional study with multistage random sampling was done on urban school adolescents and university students from public schools and Dire Dawa University in Dire Dawa city, Ethiopia, Africa. After translating HLS‐EU‐Q47 into Amharic by translation and back- translation, data was collected using a self-reported questionnaire from samples of 744 participants with 9% non-response rate in October and November, 2018. Confirmatory factor analysis and correlation analysis was done using SPSS and AMOS. Goodness of fit indices, item-scale convergent validity, Pearson correlation coefficient, floor and ceiling effects, Cronbach's alpha and split-half spearman-brown coefficient was computed taking the cut-off values from guidelines and literatures. Ethical issue was contemplated and informed consent was obtained from institutions and participants. Result: Amharic version of HLS- EU-Q47, (HLS-Amh) was reliable but weak for its validity to measure health literacy among urban school adolescents and university students in Dire Dawa, Ethiopia. Goodness-of-fit indices (GFI, AGFI, CFI and IFI) were within range of 0.90-0.80. Although, RMSEA indices were less 0.10, others have made it insufficient to be said as a good model-data fit and was not tolerable for its validity, and the model lacked strength to meet the model-fit indices satisfaction with higher apparent floor/ceiling effects. However, it showed high levels of internal consistency of reliability with relatively higher Cronbach’s alpha coefficient (α=0.910). Conclusions: HLS-Amh was reliable but weak for its validity on these population groups. It can be used for a general survey on awareness and knowledge other than screening substantial and clinical related inquiries. It needs further adaptation and validation for comprehensiveness for demographic, multi-lingual and cultural contexts in Ethiopia.