Background <p>The aim of this study is to assess the factors associated with psychiatric comorbidities in patients with drug-resistant epilepsy (DRE).</p> Method <p>This is a retrospective study conducted at King Abdullah Medical City in Makkah. Patients with confirmed drug-resistant epilepsy between 2019 and 2023 were included.</p> Results <p>A total of 147 patients were included in the study. 32 patients (21.7%) were diagnosed with a psychiatric comorbidity. The most frequently diagnosed disorders were major depression (MD) (5.4%), generalized anxiety disorder (GAD) with MD (4.1%), GAD alone (4.1%), psychotic disorder (4.1%), and schizophrenia (2%). Factors associated with psychiatric comorbidities included age (<i>p</i> = 0.049), duration of epilepsy (<i>p</i> = 0.048), salaried income (<i>p</i> = 0.046), and the number of antiseizure medications (ASMs) (<i>p</i> = 0.001). In multivariate logistic regression analysis, four factors were found to be statistically significant: history of epilepsy surgery (odds ratio [OR] = 5.44; 95% confidence interval [CI] 1.04–58.72, <i>p</i> = 0.048), longer epilepsy duration (OR = 1.17; 95% CI 1.02–1.32; <i>p</i> = 0.049), and number of ASMs (OR = 5.91; 95% CI 1.64–21.25; <i>p</i> = 0.007). Additionally, the presence of an MRI lesion was associated with a lower likelihood of psychiatric comorbidity (OR = 0.12; 95% CI: 0.01–0.99; <i>p</i> = 0.049).</p> Conclusion <p>In clinical practice, psychiatric comorbidities are often underestimated in patients with DRE. Older age, longer disease duration, salaried income, history of epilepsy surgery, a higher number of antiseizure medications, and the absence of a structural lesion on MRI are risk factors associated with the development of psychiatric comorbidities.</p>