The activity of respiratory viruses (RVs) displays large variability in tropical regions, posing challenges for public health response strategies. Data from most RVs in south-eastern Mexico remain limited, particularly in the Yucatan Peninsula, the largest tourism hub in the country. This retrospective study analyses the regional epidemiology of RVs in Merida, the largest city in the region, using laboratory test data from a local hospital (January 2018–April 2024). Test results of 143292 RVs were collected, including 121976 for SARS-CoV-2, 19355 for influenza A and B viruses, and 1961 for 17 distinct RVs. We found that non-SARS-CoV-2 RVs circulated year-round, with higher activity in autumn and spring, while SARS-CoV-2 peaked in summer and winter. Influenza A virus, respiratory syncytial virus, and influenza B virus reached their highest activity in autumn, earlier than in other regions of Mexico. Human metapneumovirus peaked during autumn-winter. Rhinovirus/enterovirus and parainfluenza showed year-round activity, with peaks in autumn and spring. Other coronaviruses were more frequent during winter-spring. In post-pandemic years (2022–2023), adenovirus outbreaks emerged, as well as an increased prevalence of non-SARS-CoV-2 RV co-infections. This study highlights the need for region-specific public health strategies, including optimized vaccination schedules, such as for influenza A virus, and enhanced diagnostic surveillance.