Background and Objectives Tuberculosis (TB) is a global public health issue. The emergence of multidrug-resistant (MDR) TB has further complicated the situation in the form of poor treatment outcomes and costs to individuals and health-care systems. We therefore aimed to measure the prevalence and associated risk factors of MDR TB among TB patients in Makkah city. Patients and Methods This was a cross-sectional study conducted at Al-Noor Specialist Hospital, a public-sector hospital in Makkah. We included records of 158 confirmed TB patients from the list of all patients admitted in the hospital from January 2009 to January 2019 by systematic random sampling. Data were collected on socio-demographics, clinical profile and drug resistance patterns. Analysis was done in SPSS version 21.0. Results The mean age of the participants was 43.4 ± 18.7 years, and two-thirds (66.5%) were male. About 40% of the patients had chronic disease while lung disease other than TB was present in 5% patients. About 13% of cases were extrapulmonary infections. Prevalence of drug resistance was found to be 17.1% among TB patients. Among the resistant cases, streptomycin (25.9%) and isoniazid (11.1%) were the drugs most commonly affected by resistance. Prevalence of MDR TB was 5% among TB patients. Age, smoking, lung disease and previous TB were significant factors associated with MDR TB. Conclusion Prevalence of MDR TB, although comparable to current national estimates, is higher compared to previous reports. There is a need to reduce this burden through strengthening TB control programs to prevent further emergence of a public health threat of MDR TB. History of previous TB was the strongest risk factor in this study. This calls physicians, program managers and policy makers to focus on counselling and support of TB patients for compliance with the regimen to complete treatment without interruption.