Purpose: Most patients exhibiting psychiatric manifestations often remain undetected, misdiagnosed, and inappropriately managed. This cross-sectional study aims to ascertain the level of knowledge of mental illnesses among nonpsychiatric healthcare workers and their attitudes toward patients with mental illness in Makkah, Saudi Arabia. Patients and Methods: A cross-sectional study was conducted in four public hospitals in Makkah from November 2017 to February 2018. A total of 407 participants were involved. A self-reported structured questionnaire was used, and data were collected electronically. Results: Of 407 respondents, 183 (45%) were females and 244 (55%) were males. The majority of respondents were physicians with medical specialties 116 (28.5%), followed by physicians with surgical specialties 99 (24.3%). More than half 229 (56.3%) of the respondents had work experience of >10 years. Although 128 (31.4%) of the participants lacked adequate knowledge of mental illnesses, only 104 (25.6%) had relevant knowledge.154 (37.8%) respondents displayed favorable (good) attitude, whereas 82 (44.7%) displayed an unfavorable (poor) attitude toward mentally ill patients. Conclusion: The study revealed that nearly one-fourth of the participants appear to have adequate knowledge of mental disorders. However, 44.7% have an unfavorable attitude toward patients with mental illnesses. Hence, respondent professionals markedly correlated with both knowledge and attitude toward patients with mental illnesses, and the positive attitude strongly correlated with having adequate knowledge.