Background: Potential clinically significant drug-drug interactions are highly prevalent among cardiovascular outpatients due to multimorbidity and polypharmacy, posing a significant threat to patient safety. Objective: To evaluate the impact of a multifaceted clinical pharmacy intervention on the prevalence and severity of potential clinically significant drug-drug interactions in a regional hospital setting. Materials and methods: A quasi-experimental before-and-after study was conducted at the outpatient department of Tam Nong Regional Medical Center, Vietnam. We analyzed 2,400 prescriptions (1,200 pre-intervention: June-August 2025; 1,200 post-intervention: January-March 2026). Drug-drug interactions were identified using the Vietnamese National Drug Interaction Database, UpToDate/Lexicomp, and Drugs.com. The multimodal intervention included the development of a cardiovascular-specific drug-drug interactions reference list, prescriber education, and the integration of electronic clinical decision support alerts. Binary logistic regression was used to identify factors independently associated with drug-drug interactions occurrence. Results: The prevalence of prescriptions containing potential clinically significant drug-drug interactions decreased significantly from 32.4% to 12.5% (p < 0.001), representing a 61.4% relative reduction. High-severity drug-drug interactions dropped from 6.1% to 0.8% (p < 0.001), while moderate-severity interactions decreased from 26.3% to 10.2% (p < 0.001). Risk factors for drug-drug interactions included advanced patient age (≥70 years; OR 4.92, 95% CI: 3.33-7.28), high comorbidity burden (≥3 comorbidities; OR 7.13, 95% CI: 4.61-10.92), and polypharmacy (OR 3.89, 95% CI: 3.01-5.03). Additionally, prescriptions issued by prescribers with a bachelor’s degree were associated with significantly higher odds of drug-drug interactions compared with those issued by prescribers with postgraduate qualifications (OR 1.85, 95% CI: 1.43-2.39). Conclusions: The multifaceted clinical pharmacy intervention effectively reduced the prevalence and severity of potential drug-drug interactions among cardiovascular outpatients. Integrating electronic alerts with targeted education is a robust strategy for enhancing medication safety, particularly for high-risk patients.