Background: In rodent models of intracranial tumor development, evaluating the actual burden experienced by animals beyond procedural severity is essential for ethical and legal compliance. This study examined whether voluntary wheel running (VWR) could serve as a sensitive indicator of post-surgical burden following subcutaneous transmitter implantation, tumor cell injection, and tumor resection. It also assessed whether VWR supports the detection of humane endpoints. VWR outcomes were compared with body weight, clinical scores, heart rate, and activity levels recorded via telemetry. Methods: Fourteen male BDIX rats were housed individually in cages equipped with a running wheel. Under general anesthesia, telemetric devices to monitor heart rate and activity were subcutaneously implanted. After recovery, glioblastoma BT4Ca cells were stereotaxically injected into the right frontal cortex. Eight days later, the resulting tumors were microsurgically resected. Body weight, VWR, heart rate, and general activity were continuously monitored until the animals reached humane endpoint criteria, indicated by sudden weight loss and clinical deterioration. Results: On average, body weight and VWR declined significantly after all surgical procedures, with tumor resection causing the most pronounced effect. As animals approached the endpoint, a marked drop in these parameters was observed, along with an increased clinical score (p < 0.05). Activity measures supported these findings, though less consistently than weight and VWR. Conclusions: Monitoring body weight and VWR enables an effective assessment of the actual postoperative burden experienced by rats undergoing surgeries of different procedural complexity. Moreover, VWR is a valuable supplementary tool for identifying humane endpoints alongside body weight and clinical scoring.