Gastric cancer (GC) is a disease with macromolecular phenotypic heterogeneity and poor prognosis, especially for metastatic GC (mGC). Chemotherapy is the first choice for second-line treatment. However, the benefits of second-line chemotherapy are limited, so there is an urgent need for new treatment regimens to improve patient outcomes. A 65-year-old man with mGC was HER-2 positive. Standard trastuzumab, combined with chemotherapy, was given in the first-line therapy and progression-free survival (PFS) was 8 months. Second-line treatment with pyrotinib in combination with trastuzumab and chemotherapy yielded a PFS of 20 months, in sharp contrast to a median survival of 2.9-6.2 months for a majority of advanced GC patients. This case provides a meaningful reference for the second-line treatment of mGC patients with HER-2 positive. This case also provides valuable information on the response to pyrotinib plus trastuzumab of patients with brain metastases and a better understanding of dual target combination therapy applications in the future.