Economic impacts of seasonal influenza vary across US counties, but little estimation has been conducted at the county level. This research computed annual economic costs of seasonal influenza for 3143 US counties based on Census 2010, identified inherent spatial patterns, and investigated cost-benefits of vaccination strategies. The computing model modified existing methods for national level estimation, and further emphasized spatial variations between counties, in terms of population size, age structure, influenza activity, and income level. Upon such a model, four vaccination strategies that prioritize different types of counties were simulated and their net returns were examined. The results indicate that the annual economic costs of influenza varied from $13.9 thousand to $957.5 million across US counties, with a median of $2.47 million. Prioritizing vaccines to counties with high influenza attack rates produces the lowest influenza cases and highest net returns. This research fills the current knowledge gap by downscaling the estimation to a county level, and adds spatial variability into studies of influenza economics and interventions. Compared to the national estimates, the presented statistics and maps will offer detailed guidance for local health agencies to fight against influenza.