The aim of the current study was to analyse the distribution of antimicrobial drug resistance (AMR) among Pseudomonas aeruginosa (P. aeruginosa, PA) isolates from Guangdong Provincial People’s Hospital (GDPH) from 2017 to 2021, and the impact of the COVID-19 outbreak on changes in the clinical distribution and drug resistance rate of P. aeruginosa to establish guidelines for empiric therapy. Electronic clinical data registry records from 2017 to 2021 were retrospectively analysed to study the AMR among P. aeruginosa strains from GDPH. The strains were identified by VITEK 2 Compact and MALDI-TOF MS, MIC method or Kirby–Bauer method for antibiotic susceptibility testing. The results were interpreted according to the CLSI 2020 standard, and the data were analysed using WHONET 5.6 and SPSS 23.0 software. A total of 3036 P. aeruginosa strains were detected in the hospital from 2017 to 2021, and they were primarily distributed in the ICU (n = 1207, 39.8%). The most frequent specimens were respiratory tract samples (59.6%). The detection rate for P. aeruginosa in 5 years was highest in September, and the population distribution was primarily male(68.2%). For the trend in the drug resistance rate, the 5-year drug resistance rate of imipenem (22.4%), aztreonam (21.5%) and meropenem (19.3%) remained at high levels. The resistance rate of cefepime decreased from 9.4% to 4.8%, showing a decreasing trend year by year (p < 0.001). The antibiotics with low resistance rates were aminoglycoside antibiotics, which were gentamicin (4.4%), tobramycin (4.3%), and amikacin (1.4%), but amikacin showed an increasing trend year by year (p = 0.008). Our analysis indicated that the detection rate of clinically resistant P. aeruginosa strains showed an upwards trend, and the number of multidrug-resistant (MDR) strains increased year by year, which will lead to stronger pathogenicity and mortality. However, after the outbreak of COVID-19 in 2020, the growth trend in the number of MDR bacteria slowed, presumably due to the strict epidemic prevention and control measures in China. This observation suggests that we should reasonably use antibiotics and treatment programs in the prevention and control of P. aeruginosa infection. Additionally, health prevention and control after the outbreak of the COVID-19 epidemic (such as wearing masks, washing hands with disinfectant, etc., which reduced the prevalence of drug resistance) led to a slowdown in the growth of the drug resistance rate of P. aeruginosa in hospitals, effectively reducing the occurrence and development of drug resistance, and saving patient’s treatment costs and time.