Objective: To investigate the resistance to rifampicin and isoniazid and the changing trends among patients with pulmonary tuberculosis in Luohu District, Shenzhen City, Guangdong Province from 2012 to 2022, so as to provide insights into improving drug-resistant pulmonary tuberculosis control and prevention strategies. Methods: Basic information, treatment classification and drug resistance data of patients with pulmonary tuberculosis and positive pathogenic detection in Luohu District from 2012 to 2022 were collected through the Tuberculosis Surveillance System of Chinese Disease Prevention and Control Information System, and resistance rates of rifampicin and isoniazid and the changing trends were analyzed. Results: A total of 2 126 patients with pulmonary tuberculosis were collected and had a median age of 34 (interquartile range, 25) years, including 1 334 males (62.75%) and 792 females (37.25%). There were 302 patients with drug-resistance in Luohu District from 2012 to 2022, with a resistance rate of 14.21%. Among them, 60 patients were monoresistant to rifampicin (2.82%), 113 patients were monoresistant to isoniazid (5.32%), and 129 patients were multidrug resistant (6.07%). The rate of rifampicin monoresistance showed a downward trend from 2012 to 2022, while the rate of multidrug resistance showed an upward trend (both P<0.05). There was no significant tendency in the rate of isoniazid monoresistance (P>0.05). The rate of multidrug resistance among patients without Shenzhen residence was higher than that among patients with Shenzhen residence; the rates of rifampicin resistance and multidrug resistance among retreated patients were higher than those among treatment-naïve patients (all P<0.05). Conclusions The rate of rifampicin monoresistance appeared a downward trend and the rate of multidrug resistance appeared an upward trend among patients with pulmonary tuberculosis in Luohu District from 2012 to 2022. Attention should be given to non-Shenzhen residence and retreated patients.