Background and Aims Prediction of pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) for breast cancer is critical for surgical planning and evaluation of NAC efficacy. The purpose of this project was to assess the efficiency of a novel nomogram based on ultrasound and clinicopathological features for predicting pCR after NAC. Methods This retrospective study included 282 patients with advanced breast cancer treated with NAC from two centers. Patients received breast ultrasound before NAC and after two cycles of NAC; and the ultrasound, clinicopathological features and feature changes after two cycles of NAC were recorded. A multivariate logistic regression model was combined with bootstrapping screened for informative features associated with pCR. Then, we constructed two nomograms: an initial-baseline nomogram and a two-cycle response nomogram. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were analyzed. The C-index was used to evaluate predictive accuracy. Results Sixty (60/282, 21.28%) patients achieved pCR. Triple-negative breast cancer (TNBC) and HER2-amplified types were more likely to obtain pCR. Size shrinkage, posterior acoustic pattern, and elasticity score were identified as independent factors by multivariate logistic regression. In the validation cohort, the two-cycle response nomogram showed better discrimination than the initial-baseline nomogram, with the C-index reaching 0.79. The sensitivity, specificity, and NPV of the two-cycle response nomogram were 0.77, 0.77, and 0.92, respectively. Conclusion The two-cycle response nomogram exhibited satisfactory efficiency, which means that the nomogram was a reliable method to predict pCR after NAC. Size shrinkage after two cycles of NAC was an important in dependent factor in predicting pCR.