The 2022/2023 season witnessed a rapid resurgence of H1N1pdm09 in Anhui Province, China, surpassing previous years, prompting an examination of hemagglutinin (HA) gene mutations and cross-immunity in this study. Anhui Province´s surveillance data established the detection threshold for H1N1pdm09 using the Moving Epidemic Method. Joinpoint regression compared weekly percent change (WPC) rates. A total of 103 strains of H1N1pdm09 were sequenced and analyzed, and cross-reactivity was assessed using Pepitope model. The ILI% (percentage of outpatient visits for influenza-like illness) and influenza detection rate for the 2022/2023 season were 6.82% and 31.90%, respectively, which surpassed those of 2017/2018-2021/2022. The H1N1pdm09 subtype dominated this outbreak. The epidemic threshold for H1N1pdm09 was 3.53%, exceeded in the sixth week of 2022/2023, leading to a shorter but intense epidemic phase. The WPC for the 2022/2023 season reached 376.40% (95% confidence interval: 253.4%-545.8%), faster than in the prior seasons. Sequence analysis showed that a majority of the 32 strains, obtained in the 2022/2023 season, belonged to clade 6B.1A.5a.2a, with only one strain identified as 6B.1A.5a.2a.1. Cross-protection efficacy against representative strains from the 2017/2018 and 2018/2019 seasons was limited (25.54%, 34.69%). This analysis provides insights into Anhui´s influenza situation, including early warning thresholds, molecular and immune perspectives, and cost-effective prevention and control strategies.IMPORTANCEThe H1N1pdm09-associated morbidity and mortality impact negatively on the socio-economic status of the affected population. Potential modification of the genetic and antigenic traits of the virus, as it circulates, has raised concern that it may hinder a host´s immune response or vaccine efficacy. These have prompted researchers to come up with intervention measures to manage H1N1pdm09 as a pathway to ease the pressure on public health. This analysis provides insights into Anhui´s influenza situation, including early warning thresholds, molecular and immune perspectives, and cost-effective prevention and control strategies.