BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors play a significant role in type 2 diabetes mellitus (T2DM) management due to their efficacy and favorable safety profiles. Despite their growing importance, there is limited information on the knowledge and prescribing behaviors of primary care physicians in Saudi Arabia, particularly in the Qassim region, regarding the use of DPP-4 inhibitors. This study sought to assess the knowledge, attitudes, and prescribing patterns of primary care physicians concerning DPP-4 inhibitors in the management of T2DM. METHODS: A cross-sectional study was conducted involving 161 primary care physicians in the public sector from the Qassim region. Data were collected through a semi-structured and validated self-administered questionnaire that collected data on knowledge about DPP-4 inhibitors, attitudes toward their use, and prescription practices. Statistical analyses, both descriptive and inferential, were performed using the Statistical Package for the Social Sciences (SPSS) version 25 (IBM Corp., Armonk, NY, US). RESULTS: Participants showed specific knowledge gaps, but overall, most had a positive outlook. A significant majority (86.3%) were aware of the low risk of hypoglycemia associated with these agents; however, only 60.9% recognized them as a relatively new therapeutic option. Overall, physicians demonstrated positive attitudes and appropriate prescribing practices. Knowledge levels showed significant associations with physician age (<0.001), clinical experience (<0.001), qualifications (<0.001), and the availability of educational resources (<0.001). CONCLUSION: Primary care physicians in the Qassim region generally possess good awareness and favorable attitudes toward DPP-4 inhibitors. However, further targeted educational programs are essential to bridge identified knowledge gaps and enhance prescribing practices for optimal T2DM care.