Originally from Sale, Pendlebury began his sporting career in basketball and accepted a scholarship to the Australian Institute of Sport in Canberra. However, he decided to pursue competitive Aussie Rules and pulled out of the 12 man AIS basketball squad. Pendlebury was selected for the 2005 Under-18 Vic Country team. He played two of the three games and had an average of 17 possessions.
He was selected to play for eventual 2005 TAC Cup premiers Gippsland Power. He played 19 games, kicked 11 goals and averaged 22 possessions a game.Collingwood became aware of Pendlebury after Gippsland Power manager Peter Francis recommended both Pendlebury and his older brother Kristopher. Collingwood drafted Scott Pendlebury with pick five in the 2005 AFL Draft, and Collingwood's number two pick overall, whereas Kris did not play in the AFL but did captain the Collingwood side in the Victorian Football League.
Pendlebury started with the number 16 guernsey and changed to number 10 at the start of the 2006 season. He is a natural left-footer, and rarely wastes a possession, and has excellent vision that has been attributed to his years in basketball.
Pendlebury's 2006 pre-season was hampered by glandular fever, but he made a successful comeback with Collingwood's VFL affiliate, Williamstown. He made his AFL debut in Round 10 against the Brisbane Lions, and became part of a select group of footballers known for kicking their first goal with their first kick in league football. He played eight more games in the 2006 season.
Pendlebury switched to the number 10 guernsey previously worn by Blake Caracella, and gave the number 16 guernsey to newcomer Nathan Brown. Following his nine games in 2006, Pendlebury broke into the Collingwood midfield on a regular basis, averaging 18 disposals a game before he was nominated for the NAB Rising Star in Round 4. He collected a season-high 26 possessions in the 2007 Semi-Final against the West Coast Eagles in Perth, and kicked a crucial goal during extra time.
Throughout the 2007 season, he was compared with Geelong rookie midfielder Joel Selwood.[by whom?] Both were close favourites for the 2007 NAB Rising Star with Selwood eventually winning by seven votes.
On 9 May 2008, Pendlebury was selected in the Victorian Squad for the AFL Hall of Fame Tribute Match, with team-mates Josh Fraser and Heath Shaw. Despite playing only half of the match, he collected 19 disposals with a 79% efficiency rating. 
Pendlebury was an important factor in Collingwood's 86-point victory over reigning premiers Geelong. 
Pendlebury played his 50th game on 9 August 2008 against St Kilda in Round 19. He finished third in Collingwood's 2008 Best and Fairest count.
Pendlebury became more prominent in 2009. He collected a career high 39 disposals against Melbourne Football Club on the Queens Birthday and won the Women's Round medal. He had a career high 22 kicks against the West Coast Eagles and another career high 20 handballs against the Richmond Football Club. Despite missing a few games due to injuries, he was still shortlisted for selection as an All-Australian. He had an average of 26 disposals a game (13 kicks and 13 handballs)and averaged 2 goals per 5 games. His season ended with a cracked fibula bone injury in the Qualifying final.
In 2010 Pendlebury won a spot in the All-Australian team and won the ANZAC Medal. He polled 21 votes in the 2010 Brownlow Medal, to finish in fourth position. He won the 2010 Norm Smith medal when Collingwood won the premiership.
In 2011 Pendlebury won his second ANZAC Day Medal as best-on-ground in Collingwood's 30-point win over Essendon. Three weeks later, against Geelong, he was controversially denied a goal from a free kick that would have won Collingwood the game. Ultimately, the Magpies lost by three points.
He capped off a brilliant year, winning the Copeland Trophy for the best and fairest player at Collingwood, and the Bob Rose Trophy for being the best Collingwood player throughout the finals.
Pendlebury finished the season with 15 brownlow votes, down on his 24 from the previous year and helped the Magpies to a Preliminary Final, where they eventually lost to the Sydney Swans. He finished second in the Copeland Trophy to winner Dayne Beams and in front of three time champion Dane Swan. He was also included in the All Australian for the 3rd year running alongside team mates Swan and Dayne Beams.
Pendlebury improved on his 2012 season, having arguably his best and most consistent season to date. Already touted as future captain of the Collingwood Football Club, Pendlebury helped lead the club brilliantly in 2013 and although Collingwood lost the Elimination final loss to Port Adelaide, Pendlebury won his second Copeland Trophy beating former champion Dane Swan. He also had 21 votes in the Brownlow, only losing out to team mate Dane Swan for the highest votes for the Magpies. Pendlebury once again was included in the All Australian Squad being named on the wing. This was his fourth consecutive inclusion in the team.