This study aimed to systematically assess the evidence regarding the efficacy of spiritual interventions on quality of life and spiritual well-being among patients with cancer. PubMed, CINAHL, PsycINFO, Embase, MEDLINE (via EBSCOhost), and Web of Science databases were searched. Studies were included if these reported spiritual interventions for adult patients with cancer. Quality assessment of the included studies were conducted using the Critical Appraisal Tool for Randomized Controlled Trials from Joanna Briggs Institute. The review was registered in PROSPERO (CRD42021277873). A total of ten randomized controlled trials that enrolled 1332 patients with cancer were included. Spiritual interventions of the included studies involve: meaning-centered, mindfulness, dignity therapy, yoga, spiritual counseling, and body-mind-spirit group therapy. The length of the interventions ranged from 2 to 12 sessions. Further analysis shows spiritual interventions improve spiritual well-being (N = 479, 95% CI = 0.36 to 1.97, p < 0.0001), and Quality of Life (N = 706, 95% CI = 0.07 to 0.40, p = 0.004). Spiritual interventions are proved to be effective to improve spiritual well-being and quality of life. It is important for nurses and healthcare professionals to integrate spiritual interventions to improve the quality of care including patients' spiritual well-being and quality of life.