Background: Acute respiratory infections (ARI) caused by a wide range of etiologies represent a significant public health challenge worldwide. Objectives: In this study, we aimed to evaluate the characteristics of ARI caused by various respiratory pathogens among patients admitted to intensive care units (ICUs) in a referral hospital in Iran during the first four waves of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Methods: A total of 395 patients with ARI were enrolled, all hospitalized in the ICUs of Nemazi Teaching Hospital, affiliated with Shiraz University of Medical Sciences in Shiraz, Iran, over a 13-month period from April 2020 to June 2021. Real-time polymerase chain reaction (RT-PCR) assays were used to detect SARS-CoV-2, influenza viruses, respiratory syncytial virus (RSV), Mycoplasma, and Chlamydia in nasopharyngeal fluid (NPS) samples. The demographic and clinical data, including underlying diseases, were also considered. Results: Of the 395 patients, 209 (53.7%) were male, and the mean age was 32 ± 27 years. An etiology was detected in 63 (16%) patients, with 53 testing positive for SARS-CoV-2 and 5 each for Chlamydia and Mycoplasma. No RSV or influenza infections were detected. The highest rate of COVID-19 was observed among adults aged 36 to 65 years (5.31%), while the lowest rate was in children under 5 years old (0.3%). Shortness of breath was the most common symptom in SARS-CoV-2-infected patients (P-value ≤ 0.001). Of the total patients, 146 (37%) had at least one underlying disease, with diabetes being the most common (8.1%). Conclusions: The absence of RSV and influenza infections, along with a notable number of Chlamydia and Mycoplasma infections during the first four waves of the SARS-CoV-2 pandemic, emphasizes the importance of continuous surveillance of the etiologies of ARI during respiratory pandemics. This information is critical for guiding appropriate infection control measures and selecting empirical antibiotic regimens.