Develop a scheme
Find a formation that has more than one or two plays in it that you can use to attack the defense with. When you are on offense, you want to do these things:

1- Run the ball
2- Beat Man defense
3- Beat Zone defense
4- Beat blitzing defenses
5- Stretch the field

If you can do all of these things from the same formation, or similiar formations, your offense will be that much more effective, and you will be looking like the real deal out on the digital gridiron!