Knee osteoarthritis (OA) is a chronic degenerative joint disease that causes pain and adversely affects functional status and holistic well-being. This randomized controlled trial investigated the effect of Reiki on pain, functional status, and holistic well-being in patients with knee OA. The sample consisted of 42 patients. The control group received standardized treatment only, whereas the intervention group received face-to-face Reiki (nine positions; 39 minutes) and distance Reiki on two consecutive days in addition to standardized treatment. The Reiki group had lower pain scores than the control group as measured by the Visual Analog Scale (p < .001) and the Western Ontario and McMaster Universities Arthritis Index pain score (p < .001). Those participating in the Reiki group had improved holistic well-being scores specifically for the subscales of Sadness, Perception of Sadness, Spiritual Disruption, Cognitive Awareness, and General mood. Reiki is a safe, noninvasive, and cost-effective alternative treatment technique that has the potential to reduce symptoms of pain and improve holistic well-being in patients with knee OA.