Best Bet For Saturday (March 21st): March Madness Second Round Predictions

The NHL had started to sour on me and my bets, so the NCAA Tournament came around at just the right time for my daily best bets. After going 2-0 over the first two days of action, I’m looking to build up a proper heater. For my best bet for Saturday, March 21st: March Madness Second Round Predictions, we’re headed to the KeyBank Center in Buffalo, New York, for Second Round action in the East Region. Let’s get this money!

Best Bet For Saturday (March 21st): March Madness Second Round Predictions

#6 Louisville Cardinals vs #3 Michigan State Spartans

Start Time: 2:45 PM EST

This portion of the East bracket has gone to chalk, as the Louisville Cardinals and the Michigan State Spartans made it through the first round (the Cardinals got pushed by #11 South Florida, however). Now, two revered programs, the ACC’s Cardinals and the Big Ten’s Spartans, will battle for a spot in the Sweet Sixteen.

This should be a tight game – tighter than the spread indicates, but more on that later – with Louisville having a stronger offense, and Michigan State having the better defense. While the Cardinals are on a strong 4-1 run over their past five games, the Spartans stumbled into the tournament, having lost two straight Big Ten games.

After crunching the numbers, my line is Michigan State -0.5, so the Cardinals plus the points is my best bet for Saturday.

Best Bet: Louisville +4.5 (-105)

Best Bet Overall 2026 Record: 52-27 (66%)
Profit (based on $100/bet): $1,330.24
Return on Investment: 17%