This phrase is used in sports betting to describe a bet against the betting line. Every game has a betting line which favors one of the teams. Betting against the spread means the bettor is using the points and betting on the underdog.
Betting against the spread is a good betting strategy when the point spread is low, or the bettor believes the team they are betting on can beat their opponent by at least the point spread advertised. If the bettor believes the team will win big, betting against the spread will result in a huge payout. An example of betting against the spread would be if a wager that the New York Giants (-7) would beat the New England Patriots (+7). That means the Giants would have to win by more than 7 points for the individual to win his bet.