Drug-Drug Interaction Knowledge, Practices, and Barriers in Community Pharmacies: A Cross-Sectional Study from Jazan Region, Saudi Arabia

(1) Background: Drug-drug interactions (DDIs) are a frequent cause of medication-related harm, particularly in ambulatory care. Community pharmacists are uniquely positioned to identify and manage these risks. This study assessed DDI knowledge, practices, and barriers among community pharmacists in the Jazan Region, Saudi Arabia. (2) Methods: A structured, self-administered questionnaire was distributed to community pharmacists. The survey assessed DDI knowledge using 26 clinically relevant drug pairings and included questions on professional behavior, training exposure, software use, and educational needs. Descriptive and inferential statistics were applied to identify associations between knowledge scores and demographic or practice-related variables. (3) Results: A total of 219 pharmacists participated in the study. The mean knowledge score was (9.63 ± 4.58) out of 26, reflecting suboptimal to moderate awareness. Female pharmacists demonstrated significantly higher DDI knowledge scores than males (10.74 ± 5.4 vs. 9.08 ± 4.2; <i>p</i> = 0.016). Knowledge scores also differed significantly by academic qualification (<i>p</i> < 0.001), with PharmD holders scoring higher than B. Pharm and postgraduate degree holders. Pharmacists with less than 10 years of experience had significantly higher scores compared with those with longer practice duration (<i>p</i> = 0.002). Additionally, pharmacists who graduated from Saudi institutions scored higher than those trained outside Saudi Arabia (10.22 ± 4.7 vs. 8.44 ± 4.2; <i>p</i> = 0.005). Pharmacists who had received professional development training and those who attended workshops regularly also scored significantly higher. Familiarity with guidelines showed a positive trend. Reported barriers to effective DDI counseling included time constraints, limited patient understanding, and poor collaboration with prescribers. Self-rated awareness of DDIs was positively associated with actual knowledge scores. Pharmacists expressed strong preferences for workshops, online courses, and webinars as future training formats. (4) Conclusions: Pharmacists in the Jazan Region demonstrate moderate awareness of DDIs, with variation influenced by training, experience, and qualifications. Enhancing access to structured professional development and integrating clinical decision support tools could strengthen pharmacists' role in preventing DDIs in community practice.