Background <p>Neoadjuvant chemotherapy is the recommended treatment for stage II and III triple-negative breast cancer (TNBC). We aimed to study the role of phosphorylated Nrf2 (pNrf2) in the responses to neoadjuvant chemotherapy in TNBC patients.</p> Methods <p>A prospective observational cohort study was performed in stage II and III TNBC patients who were scheduled for neoadjuvant chemotherapy between January 2017 and December 2021. The pre-treatment characteristics, including age, menses, tumor size and stages, and lymph node metastasis, were collected. The pNrf2 expression was determined by immunohistochemistry examination of tumor specimens obtained by pre-treatment core-needle biopsy. Post-treatment responses were evaluated as the clinical outcomes (RECIST) and pathological outcomes (Miller–Payne grading). Patients were assigned into either the low or high Nrf2 expression group. Their clinical characteristics and treatment responses were compared. Multivariate logistic regression analysis was performed to study the association between pNrf2 and pathological outcomes.</p> Results <p>In total, 59 patients were included, with a mean age of 52.5 years old. There were 29 patients in the low pNrf2 group and 30 in the high pNrf2 group, respectively. The pre-treatment characteristics were comparable between the two groups. Compared with the low pNrf2 expression group, the high pNrf2 expression group had poorer clinical and pathological responses (<i>P</i> = 0.010 and &lt; 0.001, respectively). Multivariate logistic regression analysis showed that the pNrf2 expression was negatively associated with the pathological response to neoadjuvant chemotherapy (odds ratio 0.033, 95% confidence interval 0.006–0.187).</p> Conclusions <p>In patients with TNBC, the pre-treatment pNrf2 expression was negatively correlated with the response to neoadjuvant chemotherapy.</p>