Abstract Objective Adherence to pain medication in patients with cancer is crucial for successful pain therapy. This review aimed to investigate the rate of adherence, which factors influence adherence, whether adherence differs in diverse patient populations, whether there are methods to improve adherence, and the relationship between adherence and pain relief. Methods This review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE/PubMed, Embase, Web of Science, Cochrane, and ClinicalTrials.gov were searched. All types of studies investigating adherence of patients with cancer, factors influencing adherence, and methods to improve adherence to pain medication were included. They were first screened on title and abstract and thereafter on full text. Selected articles were subjected to a quality assessment according to the PRISMA checklist. From included articles, study characteristics and outcomes were extracted. Results Of 795 articles, 18 were included. Different methods were used to measure adherence, which led to adherence rates ranging from 8.9% to 82.0%. White Americans and men were found to be more adherent than African Americans and women. Because of various barriers, adherence is often suboptimal. Fear of addiction, physiological and harmful effects, tolerance, and disease progression are common concerns. Interventions, such as pain education booklets, pain consults, and specialized nurses, may be beneficial to increase the adherence. Lower adherence rates were associated with lower pain relief. Conclusion Adherence of cancer patients to pain medication is suboptimal. Health care workers should focus on addressing barriers to increase adherence to obtain better pain relief.