Background Digital interventions offer vital support for patients with cancer through education, behavior change, and monitoring. Despite their potential, patient adherence to and engagement with these self-help interventions is challenging. Factors like user characteristics, technology, and intervention design influence adherence and engagement. Existing reviews have gaps in exploring diverse factors associated with adherence in cancer care. Objective This systematic review aims to identify factors influencing adherence to and engagement with digital interventions with self-help components in cancer care. It examined sociodemographic, psychosocial, health-related, and intervention-related factors that affect patients’ adherence to and engagement with these digital health solutions. Methods Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a search was conducted across PubMed, Embase, Cochrane Library, and PsycINFO to find studies published from January 2010 to September 2021. The studies included in this review focused on adult patients with cancer using digital interventions with self-help features. Data were extracted and synthesized using a standardized approach. Factors associated with adherence were synthesized according to their type—sociodemographic factors, psychosocial factors, health-related factors, technology-related factors, and intervention-related factors. Results Among 9386 studies initially screened, 61 (0.6%) were eligible for analysis. These studies covered diverse eHealth intervention types, cancer types, and outcome measures. Investigating the determinants of adherence to and engagement with digital interventions was the main objective for 43% (26/61) of the included studies. Adherence and engagement were gauged using varied measures, such as dropout rates, log-ins, and self-reported measures. Results regarding factors associated with adherence and engagement were inconsistent across studies. Most sociodemographic (eg, age) and health-related factors (eg, cancer stage) yielded mixed outcomes. However, comorbidity consistently predicted lower adherence and engagement. Results regarding psychosocial factors were more stable across studies. Specifically, higher social support was associated with lower adherence and engagement. Finally, intervention-related factors like intervention type or human support showed conflicting results. Adopting an intersectional perspective revealed that specificities vary according to intervention goals and the operationalization of adherence versus engagement, with women being more adherent and engaged than men in interventions targeting distress. When focusing on adherence rather than engagement, older patients were more adherent than younger patients. Conclusions This review highlights the complexity of adherence to and engagement with digital interventions in cancer care. While some factors, notably comorbidities and low social support, were consistently linked to adherence and engagement, others displayed mixed associations. The review underscores the need for standardizing measures, investigating specific intervention features, and enhancing study quality to optimize digital interventions for patients with cancer. Further research is crucial to better understand and improve adherence to digital health solutions in cancer care. Trial Registration PROSPERO CRD42021281028; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=281028