Defense may just be the hardest part of the game to master. But once you've got it down, it will become the cornerstone of your gameplay.
The one thing that I have to say first is that skill at defense comes with practice. The more you play, the more likely you are to know whom the game will let you control when the ball is hit in a certain spot.
When preparing for a throw, don't constantly hold your finger on the Control Pad. If you have to move to the ball, first move to the ball and field it. Then, lift your fingers off both the Control Pad and the A button and drop them down simultaneously. This will help your throwing ability infinitely.
Learn to scale the wall and where to scale it. The perspective of the camera has often thrown me off and I've been unable to take away a homerun because I scaled in the wrong spot.
Don't throw the ball around. If there's a runner rounding third and the ball has yet to be fielded by an outfielder, don't try to gun it home when he grabs it. All that does is allow the batter to try to take the extra base.
Practice makes perfect.