This study aimed to determinate characteristics of drug resistance from patients with extra-pulmonary tuberculosis (EPTB). Patients were retrospectively studied from January 2020 to December 2021. All the isolates were cultured, tested drug susceptibility, and detected the gene mutation using whole genome sequencing. The correlations of whole genome sequencing, pattern of DR, patients' distribution, and transmission were analyzed. 111 DR-EPTB isolates included pre-XDR-TB (53.2%), MDR-TB (29.7%), and poly-DR-TB (12.6%). The resistant drugs were INH followed by RFP and SM. The genotypes of 111 strains were lineage 2 and lineage 4. _p.Ser315Thr was main gene mutation for resistance to INH; _p.Lys43Arg for SM, _p.Ser450Leu for rifampicin, _p.Met306Val for ethambutol, _p.Asp94Gly for FQs, and _p.Thr76Pro for PZA. The residence was a significant risk factor for cluster transmission by patients and phenotypic DR types of strains for lineage 2 transmission. In the local area of southwest China INH, rifampicin and SM were main drugs in patients with DR-EPTB. _p.Ser315, _p.Ser450Leu, and _p.Lys43Arg were main gene mutations. Phenotypic DR types and residence were main risk of transmission.