Introduction: The misuse and overuse of antibiotics have led to a significant increase in antibiotic-resistant bacteria, posing a major threat to global health. Digital health interventions (DHIs) have been proposed as innovative solutions to enhance antibiotic use and combat resistance. This systematic review aimed to evaluate the effectiveness of DHIs in improving antibiotic stewardship and reducing the prevalence of antibiotic-resistant bacteria. Methods: A comprehensive search was performed across multiple electronic databases, including PubMed, Embase, CINAHL, Cochrane Library, and Web of Science, focusing on studies published in the last years up to 2022. Only interventional studies, such as randomized controlled trials and quasi-experimental studies, that investigated the impact of DHIs on antibiotic prescribing patterns, adherence to treatment regimens, or reduction of antibiotic resistance were included. The review followed a rigorous methodology, including a detailed assessment of study quality and data extraction processes. Results: Eleven studies were included in the review, demonstrating a diverse range of DHIs from EHR-integrated clinical decision support systems to mobile health applications. Key findings include a reduction in unnecessary antibiotic prescriptions by up to 35%, an increase in adherence to antibiotic prescribing guidelines by up to 22%, and an improvement in patient adherence to antibiotic regimens by up to 20%. These results highlight the potential of DHIs to significantly impact antibiotic use and resistance in clinical settings. Conclusions: DHIs represent a promising avenue for improving antibiotic use and combating resistance. The evidence from this review supports the integration of digital tools into antibiotic stewardship programs as an effective strategy to address one of the most pressing public health challenges. Further research is needed to explore the implementation of these interventions across different healthcare contexts and to optimize their effectiveness.