Since the tournament was expanded in 1985 to include 64 teams, No. 1 seeds have compiled a 114-0 record against teams seeded 16th.
That record was briefly placed in jeopardy earlier Thursday when Gonzaga struggled to get past Southern University, but Louisville had no trouble against the Aggies.
North Carolina A&T managed just six points during the opening 8 minutes and Louisville raced to a 47-31 halftime lead. The Aggies also endured a stretch of more than 6 minutes without scoring in the second half and produced only 17 points during the final 20 minutes.
The Cardinals will take on Colorado State in the third round on Saturday after the Rams fought off Missouri 84-72.
Smith scored 23 points while playing just 27 minutes. He hit 10-of-16 from the field and was one of just two Cardinals to reach double figures. Wayne Blackshear added 12 points for Louisville (30-5), which shot 56 percent from the field.
North Carolina A&T (20-17) defeated Liberty in the opening round of the tournament on Tuesday to earn its meeting with Louisville.
Freshman Bruce Beckford scored 12 points to lead the Aggies.