The purpose of this study was to evaluate the capacity of diffusion-weighted magnetic resonance imaging (DW-MRI) for early prediction of pathological response in breast cancer patients undergoing neoadjuvant chemotherapy (NCT). This prospective unicentric study evaluated 62 patients who underwent NCT. MRI was performed prior to the start of treatment (MR1), after the first NCT cycle (MR2), and upon completion of NCT (MR3). Pathological response was used as the gold-standard. Patients' median age was 45.5 years and the median tumor size was 40 mm. Twenty-four (38.7%) tumors presented complete pathological response (pCR). The percent increase in apparent diffusion coefficient (ADC) value between MR1 and MR2 was higher in the pCR group (p < 0.001). When the minimum increase in ADC between MR1 and MR2 was set at 25%, sensitivity was 83%, specificity was 84%, positive predictive value was 77%, negative predictive value was 89%, and accuracy was 84% for an early prediction of pCR to NCT. Meanwhile, there were no significant changes in major tumor dimensions between MR1 and MR2. In conclusion, an increase in ADC after the first cycle of NCT correlates well with pCR after the chemotherapy in our cohort, precedes reduction in tumor size on conventional MRI, and may therefore be used as an early predictor of treatment response.