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The north region of Brazil is characterized by significant vulnerabilities, notably surpassing national poverty indicators. These disparities exacerbated the impact of respiratory illnesses on the healthcare system during the COVID-19 pandemic, particularly in areas with limited healthcare resources, inadequate infrastructure, and barriers to healthcare access. The crisis was further influenced by multiple lineages that emerged as significant virus variants associated with increased transmissibility. Within this context, our ecological study focused on analyzing the epidemiological evolution of COVID-19 in the state of Acre. We constructed time-series trends in incidence, lethality, and mortality from March 2020 to December 2022 using the Prais–Winsten regression model. Our findings revealed that in 2020, there was an increasing trend in incidence, while mortality and lethality continued to decrease (p < 0.05). In the following year, both incidence and mortality decreased, while lethality increased at a rate of 1.02% per day. By the end of 2022, trends remained stationary across all rates. These results underscore the importance of ongoing surveillance and adaptive public health measures to bolster the resilience of healthcare systems in remote and vulnerable regions. Indeed, continuous monitoring of the most predominant SARS-CoV-2 lineages and their dynamics is imperative. Such proactive actions are essential for addressing emerging challenges and ensuring effective responses to adverse situations. [ABSTRACT FROM AUTHOR]