Background and Aims: Effective management of patients’ pain, anxiety, and discomfort during colonoscopy is crucial for successful completion of the procedure, patient adherence to follow-up examinations, and patient satisfaction. Virtual reality (VR) interventions, as a nonpharmacologic and innovative solution, have demonstrated promising results in managing these outcomes. Nevertheless, there is limited evidence on their effectiveness and implementation. This trial aimed to test clinical effectiveness and identify factors to facilitate the implementation of VR during colonoscopy. Methods: A hybrid type 1 effectiveness implementation, parallel randomized controlled, open-label trial was conducted. Fifty patients were randomized (1:1) to a VR or a control group. The effectiveness (pain, anxiety, discomfort, medication use, and satisfaction) and implementation (reach, adoption, implementation, and maintenance) outcomes were assessed before, during, and after colonoscopy. Results: Patients in the VR group reported significantly lower pain (P = .043) and discomfort (P <.0001) during colonoscopy, had a higher number of completed colonoscopies without sedation (P = .003), and showed higher satisfaction (P = .032). The major barrier to the implementation and maintenance of the VR intervention was inadequate VR content design. Staff were most worried about altered patient communications, unclear responsibilities, increasing workload, and patient safety. Patients expressed willingness to reuse VR glasses and to suggest them to other patients. Conclusions: VR can be used as a nonpharmacologic method for pain management and for overcoming anxiety and discomfort during colonoscopy. VR can improve patients’ satisfaction and diminish the need for sedative medications; accordingly, it has the potential to promote cooperation and compliance among patients and increase screening colonoscopy rates. (Clinical trial registration number: NCT05723861.)