First, you have to understand that playing the CPU and other users is completely different. A human mind is way more brillant that Madden's AI so you'll have to start the chess game if you want to win!
Let's start with the base: play selection.
I guess you always chose the plays you wanted to use, regardless of the formations, when playing the CPU. Well, if you're playing a human, you'll have to mix your stuff. What I mean is, if you're coming out in Singleback Big using one play, the opponent will figure out how you make it work and he'll shut it down.
Second: user catching.
If you're playing the CPU, you must think that, when you throw a pass, the defender will lose the battle if he's behind the receiver. However, against someone, you'll find out that they can take control of the player and bust the pass. That's why you want to find plays that create wide separation between the defenders and receivers.
Final: defensive coverages.
When you play the CPU, you'll find that it often comes out in plays like Cover 2, Cover 3, 2 man under, etc. Well, against a human, the plays won't be the same. You'll have more pressure and more complex coverages. Play some unranked games to get used to online defenses and make the correct reads.
I'll let a D mind talk to you about defense.