I am not a football expert, so there are probably lots of fans that can point out details, but the most significant differences I know of are size and talent.

NFL linemen are generally 30 to 50 lbs bigger than a college player. Even ends and defensive backs are much bigger and stronger. As a whole team they would dominate a college team.

And remember that most college teams only have one or two people a year get drafted, only the really skilled players get picked up by the NFL.

Talent is pretty much the summation of it.

In the college game you still have a lot of players who aren’t that wonderful, even on the very good teams. The defenses in the college game aren’t as good at picking up running quarterbacks, and more often than not the QB is simply more talented/faster/etc and can beat those defenders for huge gains. This allows college offenses to run option-spread (which is much more run heavy than pass heavy), simply because hardly anyone in the college game has the talent to contain it.

When you get to the NFL though, you have rosters built from the best of the best of the last 10 or so years. The QB is not necessarily (and often times isn’t) the best player on the field. The 11 guys lined up on defense are very likely just as good or better. They can pick up on the run and stuff the QB before he breaks for more than a few yards. And even if he breaks one, the tackles are much more powerful, and the QB isn’t likely to have a very long “lifespan” in the NFL taking hits like that. On top of all that, the rules in the NFL have evolved to be very pass-friendly.

That’s why you see super successful college QB’s like Tim Tebow, Troy Smith, Vince Young… go into the NFL and do diddly squat. Their running ability no longer trumps the competition, and their passing game simply isn’t up to snuff to compete with the guys who ran pro-style or west coast in college. There are exceptions, Mike Vick or Cam Newton in his first year or two… but I can’t think of the last time the best QB in the NFL was a guy who ran a spread-option offense in college, like what largely dominates the college game today.

@tedd is right—it’s the spread option that so many college teams use.

@zenvelo makes the case that a team of larger men will dominate the smaller college teams.
He apparently hasn’t heard of the San Francisco Offense.
The idea there is a smaller player can move faster, and won’t tire as easily. Yes, they can be manhandled by the other team, but the idea is to move the ball forward, and a faster team can do that.

Football offenses are more dividable by philosophy than pro vs. college. However, certain philosophies tend be used more in college than in the NFL, to adjust for the differences in size and talent of NFL defense. An interesting example of a pro offense running a college-style offensive scheme was the Denver Broncos last year running the spread option with Tim Tebow.

Most NFL offenses use a Pro-Style or Smash-Mouth offense, though most coaches use combinations of offenses to better suit their players’ talents and to fool the best defenses in the world. The strength of NFL defenses has led to more and more complex offensive schemes using multiple philosophies and even allowing for players tailor suited to one philosophy (ex. a Wildcat QB) to make NFL rosters in specialty roles. The NFL offense has become increasingly passing oriented. College offenses are often simpler and more run-dependent, and often use just one or two offensive philosophies. Bottom line: NFL offenses are much more complicated, and the major difference is an increased dependency of passing.

Descriptions of modern offensive philosophies in American football:
_A smash-mouth offense is a run-heavy play-calling style that aims to maximize a team’s time of possession by referring mostly to a strong running game. It’s used mostly in the NFL (though teams such as Fresno State and Iowa use it). It’s most beneficial for a team with a strong running back (Jacksonville, Tennessee are good examples).

A wing-T offense is rarely used at a college of pro level, and is used in 2 types: the Delaware (named after the college that started it) – which uses 2 RBs and a QB and involves some passing; and the Bay City, which uses 3 RBs and a QB and is mostly used for running plays and run fakes.

The option is a play-style that requires quick-thinking and talented players, and typically relies on a QB and running backs with a good blocking scheme to run plays based on reaction to the defense. It’s used mostly in college (popularized by the Oklahoma “wishbone option” originally) and is heavily used by Georgia Tech, and the service academies (mostly Air Force and Navy). It is very rarely used in professional play, as it is often seen as a “simple” offensive scheme.

A pro-style offense is a loose term for any offense used by college and high school teams that is meant to mimic an NFL offense. It’s not heavily utilized at college and NFL levels anymore, and is seen as more complex for leagues other than the NFL since it requires many offensive formations and players akin to playing more than one role. Tom Landry was one legendary coach who used the pro-style offense for his Dallas Cowboys. This is the typical pro-style offense most sports geeks refer to when they talk about pro vs. college philosophies.

The Coryell Offense (AKA the Air Coryell or the Vertical Offense) is an offensive set that is designed to combine the running game with deep passing. Because of this it often requires strong pass protection and diminishes the role of the TE as a pass-catcher, except in the Red Zone. It is typically used in the NFL with teams such as the San Diego Chargers under Norv Turner and the Baltimore Ravens under offensive coordinator Cam Cameron.

The West Coast offense is a passing offense that maximizes ball control by using high-percentage, short passing routes. It was developed for the NFL but has become so widely used that its to be incorporated at some level into almost every college and NFL offense.

The Run & Shoot offense was the predesessor to the modern spread offense, and was originally developed for high school football, but was later adopted by college and NFL teams.
With the development of the spread, however, it is rarely seen at higher levels of football, an example of a team in Division I play that uses it is SMU under coach June Jones.

The spread offense can be run by a pass-heavy or run-heavy offense, and is therefore beneficial to a balanced offensive attack. It’s usually run out of shotgun formations, and is always used with multiple WRs, typically utilizing the “no-huddle” strategy. Its used mainly in college play, though some NFL teams have used it with a pass-heavy offense. The spread option, used by some college teams and the Denver Broncos under Tim Tebow, derived from the spread and combines the spread philosophy with the option attack.

The Pistol offense is used out of a short-shotgun formation with a RB just behind the QB. It can be used with passing, hand-off, and option plays. It gives the QB a chance to read opposing defenses without signaling for a passing play like a normal shotgun play often does. It’s another offense typically used in college, though it has been used in the NFL to help a less-talented or injured QB.

The Wildcat offense is used with a mobile QB such as Tim Tebow, and is used in almost every level of football play in the US. It utilizes a good running QB to replace a skill player and allows for running and roll-out passing plays. The benefit is that its easily instituted into other offensive schemes. It’s typically seen in 2-QB sets in the NFL, where the backup QB comes in to run wildcat plays intermittently that the coach would not want to risk using the starting QB. Many NFL teams have backup QBs and WRs specifically suited for this offense, such as the New York Jets (Tim Tebow), Cleveland Browns (Josh Cribbs), and Buffalo Bills (Brad Smith)._