Breathlessness is a common presenting symptom in practice. This systematic review aimed to evaluate the impact of CDSS on breathlessness and associated diseases in real-world clinical settings. Studies published between 1 January 2000 to 10 September 2021 were systematically obtained from 14 electronic research databases including CENTRAL, Embase, Pubmed, and clinical trial registries. Main outcomes of interest were patient health outcomes, provider use, diagnostic concordance, economic evaluation, and unintended consequences. The review protocol was prospectively registered in PROSPERO (CRD42020163141). A total of 4294 records were screened and 37 studies included of which 30 were RCTs. Twenty studies were in primary care, 13 in hospital outpatient/emergency department (ED), and the remainder mixed. Study duration ranged from 2 weeks to 5 years. Most were adults (58%). Five CDSS were focused on assessment, one on assessment and management, and the rest on disease-specific management. Most studies were disease-specific, predominantly focused on asthma (17 studies), COPD (2 studies), or asthma and COPD (3 studies). CDSS for COPD, heart failure, and asthma in adults reported clinical benefits such as reduced exacerbations, improved quality of life, improved patient-reported outcomes or reduced mortality. Studies identified low usage as the main barrier to effectiveness. Clinicians identified dissonance between CDSS recommendations and real-world practice as a major barrier. This review identified potential benefits of CDSS implementation in primary care and outpatient services for adults with heart failure, COPD, and asthma in improving diagnosis, compliance with guideline recommendations, promotion of non-pharmacological interventions, and improved clinical outcomes including mortality.