Purpose Multidrug resistant tuberculosis is an emerging problem in many parts of the world. The aim of this study was to determine the drug resistance pattern of Mycobacterium tuberculosis complex in Oromia Region of Ethiopia. Patients and Methods A cross-sectional study was conducted from Jan 2017 to June 2018 on 450 pulmonary tuberculosis patients who visited health facilities in nine administrative zones of Oromia Region. Socio-demographic characteristics and relevant clinical information were obtained using a structured questionnaire. Line Probe Assay for first and second line drugs was used to assess the pattern of drug resistance. SPSS version 20 was used for statistical analysis. Results Median age was 26 years and 240 (53.3%) patients were males. About 24% of them were previously treated for tuberculosis. Thirty-four (7.6%) were HIV co-infected. Line Probe Assay interpretable results were obtained for 387 isolates. Thirty (7.8%) were resistant to rifampicin and isoniazid and thus were multidrug resistant isolates. Among the multidrug resistant samples, three were found to be extensively drug resistant and one was pre-extensively drug resistant. Previous treatment history (AOR 9.94 (95% CI 3.73–26.51), P < 0.001) and nutritional status below normal (AOR 3.15 (95% CI 1.13–8.81), P < 0.029) were found to be associated with multidrug resistance. The chi-square tests have shown that there was a significant difference between the BCG vaccinated and the non-vaccinated in developing multidrug resistant tuberculosis at P = 0.027. Conclusion The proportion of multidrug resistance is above the WHO estimate for the country, Ethiopia, and the fact that some zones were at risk of transmission of extensively drug resistant tuberculosis warrant great attention of the control program holders even though it has to be verified through the conventional method.