Current approaches to breast cancer therapy include neoadjuvant systemic therapy (NST). The efficacy of NST is measured by pathologic complete response (pCR). A patient who attains pCR has significantly enhanced disease-free survival progress. The accurate prediction of pCR in response to a given treatment regimen could increase the likelihood of achieving pCR and prevent toxicities caused by treatments that are not effective. Th early prediction of response to NST can increase the likelihood of survival and help with decisions regarding breast-conserving surgery. An automated NST prediction framework that is able to precisely predict which patient undergoing NST will achieve a pathological complete response (pCR) at an early stage of treatment is needed. Here, we propose an end-to-end efficient multimodal spatiotemporal deep learning framework (deep-NST) framework to predict the outcome of NST prior or at an early stage of treatment. The deep-NST model incorporates imaging data captured at different timestamps of NST regimens, a tumor’s molecular data, and a patient’s demographic data. The efficacy of the proposed work is validated on the publicly available ISPY-1 dataset, in terms of accuracy, area under the curve (AUC), and computational complexity. In addition, seven ablation experiments were carried out to evaluate the impact of each design module in the proposed work. The experimental results show that the proposed framework performs significantly better than other recent methods.