Betting against the spread is the most common way to bet an NFL game. Sportsbooks set the line and you can either take the favorite laying the points or the underdog receiving them.
Last year, the New England Patriots opened as -5.5 point favorites over the Philadelphia Eagles. The Patriots would have needed to win by six points to cover the spread and to win that bet. Of course, the city of Philadelphia will remind you that it was not the case.