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Background Depression is a global public health burden, and although it is multifactorial, its development is highly associated with chronic diseases. Thus, physicians' knowledge and attitude toward depression are vital for the recognition and treatment of depression among patients with chronic illnesses. This study aims to examine physicians' knowledge and attitude toward depression in Saudi Arabia and to determine factors that significantly influence them. Methodology An online survey using a 12-item questionnaire was completed by 50 physicians between January and June 2020. Knowledge (K) and attitude (A) scores were calculated and compared nonparametrically based on scores by gender and years of experience. Results Participants' years of clinical experience was found to significantly influence the participants' K scores, with those with fewer than one year of experience having the highest K scores of all participants (p < 0.05). Years of experience had a similar influence on the A scores. Furthermore, gender was an influencing factor as male participants had higher A scores than female participants. Years of experience and gender influenced the A scores independently. Male physicians more commonly referred patients to a mental health specialist than female physicians, and had significantly higher A scores and more years of experience. There was a direct correlation between the K and A score, indicating that participants' knowledge of depression positively influenced their attitude toward depression. Conclusions In this study, participants' gender and years of experience have been identified to have a significant impact on their knowledge and attitude toward comorbid depression when treating patients with chronic illnesses. This identifies an important gap and offers preliminary insight into the readiness and practice of holistic care for patients, particularly for those treated by physicians of differing gender and experience levels. Findings further demonstrate that it is most beneficial to patients with chronic illnesses that physicians utilize a holistic approach and consider depression when developing their treatment plans. This would involve being able to detect and manage depression among their patients properly, as well as referring patients to mental health specialists when needed. Clinical guidelines should be updated to emphasize the use of depression screening tools for patients with chronic diseases., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Sayed et al.)