Chronic diseases represent one of the main causes of death worldwide. The integration of digital solutions in clinical interventions is broadly diffused today; however, evidence on their efficacy in addressing psychological comorbidities of chronic diseases is sparse. This systematic review analyzes and synthesizes the evidence about the efficacy of digital interventions on psychological comorbidities outcomes of specific chronic diseases. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic search of PubMed, PsycInfo, Scopus and Web of Science databases was conducted. Only Randomized Controlled Trials (RCTs) were considered and either depression or anxiety had to be assessed to match the selection criteria. Of the 7636 identified records, 17 matched the inclusion criteria: 9 digital interventions on diabetes, 4 on cardiovascular diseases, 3 on Chronic Obstructive Pulmonary Disease (COPD) and one on stroke. Of the 17 studies reviewed, 14 found digital interventions to be effective. Quantitative synthesis highlighted a moderate and significant overall effect of interventions on depression, while the effect on anxiety was small and non-significant. Design elements making digital interventions effective for psychological comorbidities of chronic diseases were singled out: (a) implementing a communication loop with patients and (b) providing disease-specific digital contents. This focus on “how” to design technologies can facilitate the translation of evidence into practice.