(1) Background: e-Health tools, especially in the form of clinical decision support systems (CDSSs), have been emerging more quickly than ever before. The main objective of this systematic review is to assess the influence of these tools on antibiotic use for respiratory tract infections. (2) Methods: The scientific databases, MEDLINE-PubMed and EMBASE, were searched. The search was conducted by two independent researchers. The search strategy was mainly designed to identify relevant studies on the effectiveness of CDSSs in improving antibiotic use, as a primary outcome, and on the acceptability and usability of CDSSs, as a secondary outcome. (3) Results: After the selection, 22 articles were included. The outcomes were grouped either into antibiotics prescription practices or adherence to guidelines concerning antibiotics prescription. Overall, 15 out of the 22 studies had statistically significant outcomes related to the interventions. (4) Conclusions: Overall, the results show a positive impact on the prescription and conscientious use of antibiotics for respiratory tract infections, both with respect to patients and prescribing healthcare professionals. CDSSs have been shown to have great potential as powerful tools for improving both clinical care and patient outcomes.