In rodent models with intracranial tumor formation, severity assessment and humane endpoint determination are fundamental for ethical and legal reasons. We here evaluated whether voluntary wheel running (VWR) would enable classification of severity after surgery for subcutaneous transmitter-implantation, intracranial tumor-cell-injection and resection, as well as humane endpoint detection. VWR behavior was compared to body weight, clinical state, together with heart rate (HR) and activity (Act) generated via transmitter. Male BDIX rats (n=14) were single-housed in cages equipped with a running wheel. Under general anesthesia, a transmitter was implanted subcutaneously. After recovery, glioblastoma BT4Ca cells were stereotaxically injected into the frontal cortex and the solid tumor was microsurgically resected eight days after cell-injection. VWR, body weight, clinical state, HR and Act were monitored perioperatively, then continued daily towards humane endpoint criteria, which was defined by sudden weight loss and deteriorated clinical state. All surgical interventions led to reduced VWR (p<0.05) with no difference between interventions. While clinical state was not affected, either surgery resulted in a slight but significant weight loss of 2-3% (p<0.05). Heart rate was only enhanced after transmitter-implantation and tumor-cell-injection (p<0.05). Humane endpoint was not only indicated through sudden weight loss and deteriorated clinical state, but also by gradually reduced VWR and Act (p<0.05). Together, VWR deteriorated after the different surgical procedures and therefore serves as a surrogate marker for well-being. In combination with body weight and clinical scoring, VWR may also improve precise detection of humane endpoint.