Pre-draft Despite being projected as a first-round pick in the
2009 NFL draft, Spiller decided to return for his senior season in January 2009. He was the highest drafted Clemson player since
Banks McFadden (
1940 NFL draft) and
Gaines Adams (
2007 NFL draft), both of whom went fourth overall. On August 6, 2010, Spiller signed a five-year $25 million deal ($20.8M guaranteed). Spiller was named the top running back on Buffalo's final depth chart, ahead of the recently injured
Marshawn Lynch and Fred Jackson. Lynch was later traded to the
Seattle Seahawks. On September 12, 2010, Spiller played in his first career NFL game in a home loss against the
Miami Dolphins and had seven carries for six yards. Spiller was named AFC Special Teams Player of the Week for September 26, 2010, for a 95-yard touchdown return against the
New England Patriots. Spiller had a touchdown off a pass by
Ryan Fitzpatrick. However, his rookie season was marked with disappointment as he scored no rushing touchdowns and accumulated fewer yards than running backs taken after him in the draft, including
Ryan Mathews,
Jahvid Best, and
Toby Gerhart. For his rookie year in 2010, Spiller produced 283 rushing yards, 157 receiving yards, and 1189 return yards on 56 kickoff and punt return opportunities in 14 games (1 start).
2011 season In 2011, it was announced that Spiller would trade numbers with
Leodis McKelvin, receiving the number 28 in exchange for the number 21. Spiller wore number 28 at Clemson. Heading into Week 12, Spiller hadn't gotten as much action as the Bills were planning on because of the Pro Bowl caliber season that
Fred Jackson was having, but Jackson was then placed on injured reserve, meaning Spiller would finally get his opportunity and become the Bills' starting running back for the rest of the season. In a Week 16 home game against the
Denver Broncos on December 24, 2011, Spiller had the first 100-yard rushing game of his NFL career, rushing 16 times for 111 yards and a touchdown in a 40–14 win for the Bills. Spiller finished the year with 561 yards on 107 carries, with four rushing touchdowns and a 5.2 yards/carry average. He recorded 39 receptions for 269 yards and two receiving touchdowns.
2012 season With
Fred Jackson once again missing time due to injuries, Spiller took advantage of the opportunity to have a career year. In the Bills' 2012 regular season opener against the
New York Jets, Spiller had 14 carries for 169 yards and a touchdown. In the following game against the
Kansas City Chiefs, he had 15 carries for 123 rushing yards and two rushing touchdowns in the 35–17 victory. In Week 15 against the
Seattle Seahawks, Spiller reached the 1,000 yards rushing mark for the first time in his NFL career. He accomplished the feat in 154 carries to reach the mark – the fewest carries to 1,000 yards since
Chicago Bears running back
Beattie Feathers in 1934. In the following game, against the
Miami Dolphins, he had 22 carries for 138 rushing yards. Spiller rushed for 1,244 yards on only 207 carries and scored six touchdowns; his (6.009) yards per carry average (YPC) was second among running backs to Adrian Peterson's (6.025). He also caught 43 passes for 459 yards with two receiving touchdowns. Spiller was also elected to be in the Pro Bowl as an alternate for
Baltimore Ravens running back
Ray Rice, who participated in the Super Bowl.
2013 season On August 27, 2013, Spiller took temporary leave from active status with the Bills to be with his family after the
murder–suicide by his step-grandfather Hubert Allen Jr. In Week 13 against the
Atlanta Falcons, Spiller had 15 carries for 149 rushing yards and one rushing touchdown. He had three games going over the 100-yard mark on the season. In the 2013 season, Spiller rushed 202 times for 933 yards and had 33 receptions for 185 receiving yards in 15 games (10 starts).
2014 season In Week 2 against the
Miami Dolphins, Spiller returned a kickoff for a touchdown going 102 yards. For his efforts beyond that, Spiller was named the AFC Special Teams Player of the Week. On October 19, Spiller broke his
collarbone against the
Minnesota Vikings. He was placed on injured reserve/designated to return on October 21, 2014. He returned to action against the
Oakland Raiders in Week 16. The 2014 season was a tumultuous year for the Bills' running backs, aside from Spiller's injury. Fellow running back
Fred Jackson was also injured, leaving newly signed backs
Anthony Dixon and
Bryce Brown as the only healthy running backs for much of the season.
New Orleans Saints On March 13, 2015, Spiller signed a four-year, $18 million contract with the
New Orleans Saints. The deal included $9 million guaranteed. In a Week 4 game against the
Dallas Cowboys, Spiller caught an 80-yard touchdown pass in overtime to win. It was Saints
quarterback Drew Brees' 400th career touchdown pass. In Week 8 against the
New York Giants, Spiller caught Brees' seventh touchdown pass of the game. Spiller was a healthy scratch for their season opener in 2016 against the
Oakland Raiders because fellow running backs
Travaris Cadet and
Daniel Lasco were playing bigger roles, according to coach Sean Payton. On September 13, 2016, Spiller was released.
Seattle Seahawks On September 28, 2016, Spiller was signed by the
Seattle Seahawks. He was released by the Seahawks on October 26, 2016.
New York Jets On November 2, 2016, Spiller signed with the
New York Jets. He was released by the team on December 6, 2016.
Kansas City Chiefs On February 24, 2017, Spiller signed a one-year $980,000 contract with the
Kansas City Chiefs. Throughout the 2017 season, Spiller was subject to multiple transactions causing him to be cut and signed multiple times, most recently being signed for the fifth time on January 2, 2018, the Chiefs ninth transaction in less than a year involving Spiller. He became an unrestricted free agent when the contract expired on March 14, 2018. ==Career statistics==