Functional ultrasound imaging enables sensitive, high-resolution imaging of neural activity in freely behaving animals and human patients. However, the skull acts as an aberrating and absorbing layer for sound waves, leading to most functional ultrasound experiments being conducted after skull removal. In pre-clinical settings, craniotomies are often covered with a polymethylpentene film, which offers limited longitudinal imaging, due to the film’s poor conformability, and limited mechanical protection, due to the film’s low stiffness. Here, we introduce a skull replacement consisting of a microstructured, conformal acoustic window based on mechanical metamaterials, designed to offer high stiffness-to-density ratio and sonotransparency. We test the acoustic window in vivo, via terminal and survival experiments on small animals. Long-term biocompatibility and lasting signal sensitivity are demonstrated over a long period of time (> 4 months) by conducting ultrasound imaging in mouse models implanted with the metamaterial skull prosthesis.