Research based on the similarities between canine and human mammary tumors should extend beyond clinical, pathophysiological, epidemiological, and histopathological characteristics to include applicable molecular markers with prognostic significance. However, despite shared similarities, important differences must also be considered in comparative and translational studies. The nuclear erythroid 2-related factor (NRF2), a nuclear transcription factor that regulates the expression of antioxidant proteins, is pathologically activated during carcinogenesis. The role of NRF2 in human breast cancer is well established, making it a potential prognostic marker. Objectives: This study aimed to evaluate NRF2 tissue expression in mammary neoplasms of female dogs and its association with tumor progression, other prognostic factors, and survival. Methods: A group of 57 female dogs was studied. Tissue samples of mammary glands from 10 healthy dogs and 47 dogs with mammary neoplasms (39 malignant tumors and 8 benign tumors) were examined for NRF2 immunoexpression. Clinicopathological data and immunohistochemical expression, assessed by histochemical score (H-score), were correlated. Results: NRF2 tissue expression showed a predominantly cytoplasmic distribution and a lower H-score in tumors with higher malignancy grading. Dogs with higher NRF2 H-scores had improved survival rates (p = 0.0036). Univariate analysis revealed significant associations between H-scores < 135 and behavior (p = 0.007), tumor size (p = 0.001), and Ki-67 index (p = 0.018). Conclusions: These results suggest that NRF2 also holds prognostic value in the evaluation of canine mammary tumors.