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Abstract Background The COVID-19 pandemic has changed the epidemiology of upper respiratory tract infections (URTI) and the disease profile of patients attending the emergency department (ED). Hence, we sought to explore the changes in ED physicians’ attitudes and behaviours in four EDs in Singapore. Methods We employed a sequential mixed-methods approach (quantitative survey followed by in-depth interviews). Principal component analysis was performed to derive latent factors, followed by multivariable logistic regression to explore the independent factors associated with high antibiotic prescribing. Interviews were analysed using the deductive-inductive-deductive framework. We derive five meta-inferences by integrating the quantitative and qualitative findings with an explanatory bidirectional framework. Results We obtained 560 (65.9%) valid responses from the survey and interviewed 50 physicians from various work experiences. ED physicians were twice as likely to report high antibiotic prescribing rates pre-COVID-19 pandemic than during the pandemic (AOR = 2.12, 95% CI 1.32 to 3.41, p = 0.002). Five meta-inferences were made by integrating the data: (1) Less pressure to prescribe antibiotics due to reduced patient demand and more patient education opportunities; (2) A higher proportion of ED physicians self-reported lower antibiotic prescribing rates during the COVID-19 pandemic but their perception of the overall outlook on antibiotic prescribing rates varied; (3) Physicians who were high antibiotic prescribers during the COVID-19 pandemic made less effort for prudent antibiotic prescribing as they were less concerned about antimicrobial resistance; (4) the COVID-19 pandemic did not change the factors that lowered the threshold for antibiotic prescribing; (5) the COVID-19 pandemic did not change the perception that the public's knowledge of antibiotics is poor. Conclusions Self-reported antibiotic prescribing rates decreased in the ED during the COVID-19 pandemic due to less pressure to prescribe antibiotics. The lessons and experiences learnt from the COVID-19 pandemic can be incorporated into public and medical education in the war against antimicrobial resistance going forward. Antibiotic use should also be monitored post-pandemic to assess if the changes are sustained.