Virtual Reality (VR) is an advanced human-computer interaction (HCI) technology that enables immersive experiences. Its ability to induce “flow”—a focused and rewarding psychological state—positions it as a promising tool for healthcare applications. In palliative care, VR has been explored for symptom management and enhancing quality of life, but the mechanisms underlying its effects remain unclear. This study evaluates the efficacy of a flow-based VR intervention for symptom relief in terminal cancer patients compared to standard care. It also investigates how the flow state mediates symptom improvement, contributing to the understanding of HCI design in healthcare applications. A randomized controlled trial was conducted with 116 terminal cancer patients in a palliative care unit. Participants were assigned to an experimental group receiving VR-based interventions with psychological support or a control group receiving routine psychological care. Symptoms were measured using the Chinese Edmonton Symptom Assessment System, while flow states were assessed using the Flow Short Scale. ANCOVA analysis revealed significant differences in symptom scores between groups, controlling for pre-test scores (F(1,108) = 22.6, p < .001). Mediation analysis highlighted the role of flow in symptom improvement, with significant total (β = −4.31, t = −4.07, p < .05), direct (β = −3.46, t = −3.40, p < .001), and indirect effects (β = −0.85, t = −1.99, p = .046). The findings demonstrate VR’s potential to improve symptom control, supporting its broader application in healthcare, particularly in palliative care settings.