Commercial space transportation is becoming more affordable and accessible. Consequently, we expect to see significant expansion of commercial space launch activities in the coming decade. As space vehicles travel through airspace during the launch and re-entry stages, they potentially disrupt the regular operations of traditional users. This paper estimates the potential economic and operational impacts of commercial space horizontal launch activities on airlines under various launch scenarios using predictive fast-time simulation modeling, focusing on Cecil Air and Space Port in Jacksonville (Florida) and the rules governing the national airspace system (NAS) in the United States. Our results indicate that the existing 4-hour airspace closure rule impacts a significant number of flights, resulting in flight time delays, additional flight distance and fuel burn, as well as other direct operating costs. Safely reducing the duration of airspace closures could serve as a simple solution to mitigate the impacts on airlines and other traditional NAS users. More importantly, treating our studied launch vehicle as an aircraft and opening its departure/arrival corridor to air traffic during a horizontal launch and return would potentially reduce the impacts on airlines significantly, depending on the location of the spaceport, planned flight paths and the trajectory of the launch.