Spiller was drafted by the Buffalo Bills with the ninth overall pick in the 2010 NFL draft and played in the National Football League (NFL) for 9 seasons with the Bills, the New Orleans Saints, the Seattle Seahawks, the New York Jets and the Kansas City Chiefs.

[2] At Union County High School, Spiller played along fellow Clemson teammate, Kevin Alexander.

In 2006, he was named All-First Coast boys track and field athlete of the year by The Florida Times-Union after winning FHSAA Class 2A state titles in the 100 and 200 meters.

[13] After struggling versus Florida State the following week, Spiller turned it around against North Carolina by rushing for fifty-eight yards and two touchdowns in a 52–7 rout of the Tarheels.

[14] In the following weeks, Spiller had two triple-digit rushing games as the Tigers defeated Louisiana Tech and Wake Forest.

[18] In the opening three games of the season, Spiller rushed for only eighty-five yards, including a career-worst −1–yards in a 38–10 victory over Furman.

[22] With Spiller and fellow running back James Davis, the Clemson Tigers were favored to win the opening game of their 2008 season against the Alabama Crimson Tide in the Chick-fil-A College Kickoff.

[26] On January 15, 2009, Spiller announced that he would remain for his senior year at Clemson instead of entering the 2009 NFL Draft.

He also earned his spot in the record books in another way on that kickoff return, by being one of five players to ever gain 7,000 all-purpose yards.

[33] Spiller graduated from Clemson in December 2009, becoming the first person in his family to receive a four-year college degree.

[36] Despite being projected as a first-round pick in the 2009 NFL draft, Spiller decided to return for his senior season in January 2009.

[46] Spiller was named the top running back on Buffalo's final depth chart, ahead of the recently injured Marshawn Lynch and Fred Jackson.

[48][49] 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.

[50] 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.

[52] 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.

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.

[57] With Fred Jackson once again missing time due to injuries, Spiller took advantage of the opportunity to have a career year.

[59] In Week 15 against the Seattle Seahawks, Spiller reached the 1,000 yards rushing mark for the first time in his NFL career.

[75] In a Week 4 game against the Dallas Cowboys, Spiller caught an 80-yard touchdown pass in overtime to win.

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.

[84] [85] Following his playing career, Spiller joined the coaching staff at Clemson as an unpaid graduate intern in 2020.