Large molecular antibody–drug conjugates (ADCs) are able to easily access the site of metastasis in the brain due to the edematous structure of brain metastases, facilitating considerably high concentrations of the cytotoxic component of these ADCs in the intracellular and peritumoral environment. The present study discusses the cases of two different patients. The first patient had lung adenocarcinoma with asymptomatic brain metastases, visceral metastases, and bone metastases, and was treated with Sacituzumab govitecan. The second patient had HER2- positive breast cancer with lung and brain metastases, received treatment with Trastuzumab deruxtecan. The use of ADC achieved a complete response in brain metastases in both cases. Accordingly, it is suggested that efficacy evaluations regarding brain metastases should be investigated as a separate secondary endpoint in studies conducted on the use of ADC and that brain metastases should be included as a special research topic in antibody drug design and development.