Background: Drug–drug interactions (DDIs) occur when two or more drugs are administered concomitantly, changing the pharmacokinetics or pharmacodynamics of a drug’s characteristics. Despite the advances in health technology, DDIs remain a concern to patient safety. This study aimed to (1) assess the knowledge, attitude, and practice of hospital and community pharmacists toward DDIs in Saudi Arabia and (2) examine factors associated with their practice. Methods: A cross-sectional study was conducted using an online self-administered questionnaire targeting hospital and community pharmacists working in Saudi Arabia. The study questionnaire consisted of five sections: demographics, knowledge, attitude, and practice toward DDIs, as well as pharmacy characteristics. Descriptive statistics were used to summarize the characteristics of participants as count and percentage. Chi-square tests were used to examine associations between practice variables and other independent variables. Results: A total of 131 pharmacists participated in the study. The majority were males (81.7%), aged 26–35 years (64.9%), and worked in community pharmacies (81.7%). Nearly half of the participants reported optimal practice regarding checking drug interactions before dispensing any drug. Factors associated with the practice of checking DDIs were found to be gender, perceived workload, perceived knowledge, and attitude variables. Regarding the practice of asking patients about their prescription and OTC drugs, there were statistically significant differences between hospital and community pharmacists. Conclusions: Our findings on both community and hospital pharmacists in Saudi Arabia reveal that pharmacists’ attitudes and perceived knowledge might influence the practice of pharmacists toward DDIs.