Griffen was born in Goolwa, a South Australian port town at the mouth of the Murray River and began his football career with South Adelaide. The Western Bulldogs chose Griffen in the 2004 National AFL Draft at number 3 as a priority pick. He managed 17 games in his debut season, perhaps the best debut season for a Bulldogs players since Nathan Brown in 1997 and came second in the AFL Rising Star Medal count.
The 2006 Record describes Griffen as a "defender, both in a man-marking role and as a launching pad for attacking moves". Griffen has already displayed a good deal of the latter at the midway point of the 2006 season and most football critics anticipate that he will have a long career.
He suffered a jarring knee injury in Round 11 2007, where he dislocated his kneecap in the win over the Brisbane Lions. The extent of the injury, in itself, was not season threatening although he did suffer complications from a twisted bowel, which hampered his recovery and ruled him out for the rest of the season.
In 2008, Griffen played 24 games spending more time in the midfield, averaging career highs in disposals, contested and uncontested possessions, inside 50s and clearances. He covered plenty of territory and ranked number one at the Bulldogs in inside 50s and rebound 50s combined. He also ranked third in the AFL for running bounces and equal fourth at the Bulldogs for score assists during the H&A rounds. The speedy midfielder broke open a number of games in 2008, earning maximum Brownlow votes in consecutive matches against St Kilda and Essendon in rounds three and four. Finished second in the AFL for bounces and top 10 in the Bulldogs’ best and fairest. In 2009, Griffen played well at times, winning three Brownlow Medal votes on multiple occasions, but many believe he hadn't reached his full potential.
Griffen was one of the players who spoke out regarding Jason Akermanis' controversial sacking midway through 2010 season. In the Round 14 match against Hawthorn, Griffen failed to make an effort to take a mark against Xavier Ellis 30 metres out late in the final quarter as the Hawks came from behind to win by 3 points, and he was widely criticized. Griffen made up for his mistake the following week when he was named among the Bulldogs' best in a 68-point thrashing of Carlton. On the eve of the finals, Griffen was shifted from his customary position on the wing into the midfield to replace injured teammate Adam Cooney. Although the Bulldogs were again bundled out in the Preliminary Final, Griffen was one of the stand-outs, averaging 28 possessions across the three games. At the end of the season he was proclaimed the winner of the 2010 Charlie Sutton Medal.
After another stellar season in 2012, Ryan Griffen amassed a club-record 47 possessions - 22 of which were contested in the round 21 match against the Sydney Swans. The record eclipsed the previous best of 46 set by Simon Atkins. Griffen picked up 16 touches in the first quarter. His previous best was 37 possessions.
Griffen produced possibly his best season in 2013, recording 30 or more possessions 11 times and taking out his second Charles Sutton Medal ahead of a fast-finishing Tom Liberatore. Griffen also finished 6th in the AFLPA MVP Award with 177 votes. While averaging 29 disposals per game he also achieved All-Australian honours. Ryan Griffen was also ranked #8 best player in the AFL in Mike Sheahan's Top 50 Players and the Official AFL Player Ratings. On 3 December 2013 Griffen was awarded the captaincy of the Bulldogs, taking over from skipper of 3 years Matthew Boyd.
At the end of the 2014 season, Griffen asked to join the GWS Giants. On 15 October a trade was successfully reached, reuniting Griffen with coach Leon Cameron, and players Dylan Addison and Callan Ward.