PURPOSE: In brain tumor surgery, tissue shift (called brain shift) can move the surgical target and invalidate the surgical plan. A cost-effective and flexible tool, intra-operative ultrasound (iUS) with robust image registration algorithms can effectively track brain shift to ensure surgical outcomes and safety. METHODS: We proposed to employ a Siamese neural network, which was first trained using natural images and fine-tuned with domain-specific data to automatically detect matching anatomical landmarks in iUS scans at different surgical stages. An efficient 2.5D approach and an iterative re-weighted least squares algorithm are utilized to perform landmark-based registration for brain shift correction. The proposed method is validated and compared against the state-of-the-art methods using the public BITE and RESECT datasets. RESULTS: Registration of pre-resection iUS scans to during- and post-resection iUS images were executed. The results with the proposed method shows a significant improvement from the initial misalignment ([Formula: see text]) and the method is comparable to the state-of-the-art methods validated on the same datasets. CONCLUSIONS: We have proposed a robust technique to efficiently detect matching landmarks in iUS and perform brain shift correction with excellent performance. It has the potential to improve the accuracy and safety of neurosurgery.