This study aimed to examine the effects of highway expenditure, number of transportation employees, and four work commute modes (driving alone, carpooling, public transportation, and motorcycle), and road condition on highway safety across Louisiana, the Gulf of Mexico states region, the Southern states region, and the U.S. as a whole. Data spanning from 2004 to 2021 were collected and analyzed using the Stepwise Multiple Linear Regression (SMLR) method. The analysis focused on their relationships with two key highway fatality rates: Fatality Rate 1 (number of fatalities per vehicle miles traveled (VMT)) and Fatality Rate 2 (number of fatalities per number of drivers). Eight regression equations were developed and validated. The findings will provide valuable insights for policymakers, facilitating the development of effective policies and strategies to enhance highway safety and reduce fatalities.