Having lost to their neighbours just once since 2005, Canada scored three tries and limited the U.S. to just three penalties to take a nice buffer into the return leg at home next Saturday.
The aggregate winner will automatically qualify for the World Cup while the loser has a last chance in a two-leg playoff with Uruguay.
Phil Mack scored in the opening minutes for Canada to claim an early 7-0 advantage and they extended it to 13-0 by halftime thanks to two James Pritchard penalty goals.
Chris Wyles booted a penalty for the U.S. soon after the restart but Harry Jones ran over to power Canada to a 20-3 lead.
DTH Van Der Merwe sealed the match for the visitors with a 64th-minute try.