Background:  Tuberculosis (TB) is a global public health concern, associated with high mortality worldwide. The COVID-19 pandemic interrupted diagnostic and therapeutic services. These factors could have an effect on the rates of drug resistance of Mycobacterium tuberculosis (MTB). We aimed to compare the rates of drug resistance of MTB to streptomycin, isoniazid, rifampin, and ethambutol (SIRE) drugs before and after the pandemic. Methods: This cross-sectional study was conducted with a total of 100 MTB isolates, equally divided into 2 groups: Group (A) included isolates from samples collected in 2019 (before COVID-19) and Group (B) included isolates for samples collected in 2020-2021 (after COVID-19 pandemic). We tested the drug susceptibility of all MTB isolates by the automated proportion method using the BD BACTEC MGIT 960 SIRE Kit, operated on the MGIT 960 instrument system. Results: The overall resistance of MTB isolates to the SIRE drugs was recorded at rates of 21%, 15%, 18% and 11%, respectively.   There was an observed decrease in the susceptibility to SIRE anti-TB drugs from rates of 90%, 88%, 84%, 100% to 68%, 82%, 80%, 78%, respectively, with significant increase in total multidrug-resistance (MDR) rates in Group (B) compared to Group (A) MTB isolates (P< 0.0001). Conclusion: Our study revealed higher rates of multidrug-resistance in Group B (after the COVID-19 pandemic) compared to Group A (before pandemic) MTB isolates. Control measures are urgently required with raising awareness of physicians and building laboratory capacity to detect MDR- MTB.