Smith's three scoring strikes tied a career high. He completed 11-of-19 passes for 170 yards and Frank Gore contributed 125 rushing yards and a score for the 49ers (4-1).
It was San Francisco's most decisive win since beating the Rams 48-0 Dec. 27, 1987, and was the 49ers' third straight victory -- producing San Francisco's best start since 2002.
The Bucs (3-2) got a sub-par game from Josh Freeman, who went just 17-for-33 with 187 yards and two interceptions.
Tampa Bay saw its three-game winning streak stopped.