The Xpert MTB/RIF and Line Probe Assay (LPA) tests are more and more frequently used in mycobacteria testing laboratories for the rapid diagnosis of multi-drug resistance (MDR-TB). In this study, we demonstrate the effectiveness of these tests in the Central African Republic. Rifampicin resistance cases detected by the Xpert MTB/RIF during the year 2020 are also underwent first- and second-line LPA, and a first-line of drug susceptibility testing (DST) on solid medium and we compared these results. 101 rifampicin resistance cases based on the Xpert MTB/RIF were detected. Mean age was 34 years [16–81]. The 20–40 years age group represented 73.2% and the male-to-female sex ratio was 1.9:1. Patient profiles were dominated by treatment failure cases (40.6%) followed by relapsed cases (30.7%) and new cases (18.8%). These 101 rifampicin resistance were also detected with the first-line LPA and were confirmed by the DST. Similarly, the isoniazid results obtained with the first-line LPA, were confirmed by the DST, giving a concordance of 100% for these antibiotics. Rifampicin resistance were for the most part due to the absence of the WT8 sequence (56%) and the presence of the Mut3 mutation (53.4%). The majority of the isoniazid resistance (94.2%) were due to the Mut1 mutation in the katG gene and 4.2% of the cases involved both the katG gene and the inhA gene promoter with the Mut1 mutation. The second-line LPA test no resistance to second-line antibiotics. This study demonstrated the effectiveness of the Xpert MTB/RIF and the LPA tests for the rapid diagnosis of MDR-TB in the Central African Republic. However, due to their high cost, these tests have not been extensively deployed in the country. Public authorities and their TB-partners can help make these molecular tests more accessible to fight MDR-TB in the country.