Pickett was a consensus All-American selection, adding All-State honors at Zephyrhills High. Named one of the top 25 players in the country by the National Recruiting Advisor. He recorded 119 tackles with seven sacks as a senior.
Pickett played college football at Ohio State from 1998 to 2000. He was a three year starter and played both defensive tackle positions. Pickett played in every game as a true freshman and started the final nine games at right defensive tackle. He totaled 22 stops (17 solo), two sacks, and five tackles for loss. As a sophomore, Ryan started the whole season at right defensive tackle. He also was named All-Big Ten honorable mention with career-highs of 48 tackles (34 solo) and three sacks. In Pickett's junior season, he switched sides and played left defensive tackle. He totaled 39 tackles (21 solo), three sacks and two forced fumbles in 1999. After Pickett's junior season he decided to skip his senior season and apply for the NFL draft.
Pickett was selected with the 29th pick of the first round in the 2001 NFL Draft by the St. Louis Rams. On July 28, 2001, Pickett signed a five-year, $5.995 million contract with the Rams. Pickett's contract includes a $2.615 million signing bonuses. His base salaries were $504,000 in 2001, $530,000 in 2002, $656,000 in 2003, $782,000 in 2004 and $908,000 in 2005.
In his rookie season with the Rams, Pickett took a backup role on the defensive front along with playing some special teams. In 2002, Pickett had a breakout year starting 14 games at left defensive tackle and finishing the season second on the team in tackles with 67 (45 solo). In 2003 and 2004 he maintained his above average play at the defensive tackle and nose tackle positions for the St. Louis Rams and was a vital part of their defense both in the regular season and in playoff contests.
In 2005, Pickett had his highest statistical season to date. He started all 16 of the Rams games and racked up a career high 65 tackles (47 solo), which was the highest total for any defensive lineman in the NFL that season. After the 2005 season Pickett became an unrestricted free agent.
On March 17, 2006, the Green Bay Packers signed Pickett to a four-year, $14-million free-agent contract. In his first season with the Packers, Pickett started in all 16 of the Packers regular season games and collected 92 tackles (45 solo), one fumble recovery, and a career-best seven passes defensed. In 2007 Pickett played in 14 games (14 starts) and totaled 39 tackles and recorded his first sack as a Packer. In 2008 he had 48 tackles, started all 16 games, and registered 1.5 sacks and knocked away three passes. In 2009 Pickett played the Nose Tackle position in defensive Coordinator Dom Capers new 3-4 defense.
On February 25, 2010, the Packers applied their Franchise Tag on Pickett, and signed him to a 3-year deal on March 12, 2010. Pickett mainly now plays the Defensive End position in the Packers' 3-4 defense with second-year player B.J. Raji moving to the Nose Tackle position. From time to time, he plays the Nose Tackle position.
Pickett helped anchor the defensive line during the Packer's Super Bowl run in 2010-11. He only trailed Charles Woodson as the longest tenured NFL player on the Packers' defense. He had 2 tackles in Super Bowl XLV but, more importantly, was instrumental in one of the game's biggest plays. On the first play of the fourth quarter, the Pittsburgh Steelers were trailing the Packers 21-17, but had a second-and-two at the Packers' 33-yard-line. Steelers' running back Rashard Mendenhall took a hand off and was immediately met in the backfield by Pickett. Pickett had Mendelhall wrapped up, allowing Clay Matthews to force a fumble by sandwiching Mendenhall between himself and Pickett. Packers' linebacker Desmond Bishop recovered the fumble and the Packers' offense would march down the field to extend their lead to 28-17. The Packers would go onto a 31-25 victory, bringing Green Bay their first title in fourteen years.