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Background: Although phenotypic drug susceptibility testing (DST) of Mycobacterium tuberculosis (Mtb) takes up to 6–8 weeks, little is known about how drug susceptibility is affected during this period. Methods: We performed a prospective cohort study to investigate the development of drug resistance (DR) during turnaround time (TAT), including 359 pulmonary tuberculosis (PTB) patients with a baseline DST result of an Mtb isolate collected at TB diagnosis and a follow-up DST result of an Mtb isolate collected when baseline DST result was available between 2013 and 2018. Whole-genome sequencing (WGS) was used to differentiate between acquired drug resistance, exogenous reinfection, and mixed infection. Results: Among the studied patients, during TAT for DST, 116 (32.3%) developed DR to four first-line drugs (rifampicin, isoniazid, pyrazinamide, ethambutol). Among 116 pairs of isolates included for WGS, 21 pairs were classified as acquired drug resistance with single nucleotide polymorphisms (SNPs) differences less than 12. Four pairs with an intermediate SNPs differences displayed minor differences in related genotypes and were assessed as mixed infection. The remaining 91 pairs had high SNPs differences consistent with exogenous reinfection. Conclusions: The exogenous reinfection of drug-resistant strains played a vital role in the development of DR of Mtb isolates during TAT for DST, highlighting the need for both rapid DST methods and improved infection control.