This study aimed to examine the validity and reliability of the EORTC QLQ-BR45 questionnaire among breast cancer patients in Ethiopia. This study included 248 breast cancer patients who completed the QLQ-BR45 and QLQ-C30 questionnaires. The internal reliability, test–retest reliability, and the content, concurrent, convergent, divergent, and clinical validity of the tool were examined. The statistical analyses included Cronbach’s α coefficient, Pearson’s correlation coefficient, standardised root mean square residual (SRMR), comparative fit index (CFI), t-test, and root mean square error of approximation (RMSEA). All items were marked as relevant, and item-level content validity index (I-CVI) scores ranged from 0.83 to 1. The S-CVI/Ave was calculated by dividing the sum of I-CVI values by the total number of items, which was found to be 0.94. The average CVR value was 0.76. The Cronbach’s α coefficient was 0.80 for all domains. All subscales met the minimal standards of reliability except the arm symptom scale (0.66). The test–retest reliability coefficient was 0.77 for all domains. Seven out of the 12 hypothesised scales showed positive correlations (r > 0.40) between the QLQ-BR45 and QLQ-C30 scales. Multitrait scaling analysis showed that the item-scale correlations exceeded the 0.40 criterion for item-convergent validity for 11 of the 12 hypothesised scales. The correlation coefficients between an item and its own subscale were significantly higher than with other subscales. The EORTC QLQ-BR45 had good reliability and validity, and it can be used to measure the quality of life of breast cancer patients in Ethiopia.