Whole genome sequencing has been used to investigate the genomic diversity of M. tuberculosis in the northern and southern states of India, but information about the eastern part of the country is still limited. Through a sequencing-based strategy, this study seeks to comprehend the diversity and drug resistance pattern in the eastern region. A total of 102 M. tuberculosis isolates from North East (n = 54), and Odisha (n = 48) were sequenced along with 7 follow up isolates from Sikkim. The pre-XDR and XDR isolates diagnosed as per the NTEP diagnostic algorithm were subjected for phenotypic second-line liquid culture drug susceptibility testing in MGIT-960 system. After filtering out low quality isolates based on taxonomic classification and depth of coverage, variant calling was performed. We observed a high prevalence of multi-drug resistant TB (MDR-TB) lineage 2 (52/54) isolates in northeast whereas there was a mixed representation of lineage 1 (30/48) & lineage 3 (11/48) in Odisha. The MDR-TB isolates from Sikkim posed a high rate (51/53) of fluoroquinolone resistance and pairwise SNV distances (≤10) indicating possible local transmission events in the region. We observed occurrence of genetic variations in genes associated with bedaquiline and delamanid resistance. Our findings show the diversity of M. tuberculosis vary across the eastern regions, in north eastern states lineage 2 has a dominant presence while lineage 1 and 3 has mixed representation in Odisha. The high prevalence of fluoroquinolone resistance in north eastern region associated with variations in gyrA gene and may have been caused by local transmission events based on genomic similarities.