The Carlton Football Club recruited Nicholls from the Maryborough Football Club in 1957 after recruiting his elder brother, Don, the previous year their father ensured that both brothers would play together at one club. Don played 77 senior games as a centreman for Carlton from 1956, when he was Carlton's best first-year player, to 1961.
In his first year as captain-coach, Nicholls led the Blues to the minor premiership with 18 wins and a draw, followed by Richmond with 18 wins. 1972 was the first season in which the McIntyre "Final Five" system was used, and so because Carlton finished on top of the ladder, this meant that they had to wait until the semi-final, in which they faced Richmond. The match was drawn, which in those days meant that a replay was required the following week, thus shifting every other match back another week. Richmond won the replay by 41 points, but in the post-match interviews Nicholls refused to panic:
Carlton has not hit a form slump. We just had a dismal day - our worst for the season. [...] There'll be no panic just because we went down by 41 points. There won't be more than one or two changes. [...] We will be sticking to the same players because it was they who put us where we finished at the end of the home-and-away games. [...] I know the players will redeem themselves next week. We just won't beat St. Kilda - we will win well. And if we team together as I know we can I know we are good enough to take the premiership.
Nicholls' immense size, characterised by tree trunk-like legs, earned him the nickname "Big Nick." He was appointed captain in 1963 for one season, and then again in 1968, holding the position from then until retirement. In 1972, he became captain/coach of the club, and after retirement as a player in 1974, continued coaching through 1975.
Nicholls played in three premierships, all as captain:
1973, again as captain/coach, against Richmond; in which he was felled early by Laurie Fowler, causing Nicholls to have double vision, and concussing him.
Nicholls finished his VFL career with a then-record 331 games (three state games played during Carlton games were added to his 328 Carlton games). He played for Victoria 31 times in interstate football, a record which, due to the lack of top-level interstate football since 1999, is very unlikely to be broken. Following his retirement from Carlton, Nicholls coached two seasons with the Glenelg Football Club, from 1977–1978, and one season at the Coburg Football Club (1981). He also scored 307 goals in his career.
Nicholls won the Robert Reynolds Trophy for Carlton's best and fairest player on five occasions: 1959, only his third season, and then in 1963, 1965, 1966 and 1967. In the eleven seasons from 1959 to 1969, Nicholls never placed outside the top three for the award. The trophy was renamed in Nicholls' honour in 2004. He was also named in Carlton's Team of the Century in the first ruck.
With the inception of the Australian Football Hall of Fame in 1996, Nicholls was named as one of the twelve inaugural "Legends." He was also named in the AFL Team of the Century, as the resting ruckman in the back pocket, with Graham Farmer taking the first ruck position. He is depicted contesting a boundary throw-in against Farmer in Jamie Cooper's painting the Game That Made Australia, commissioned by the AFL in 2008 to celebrate the 150th anniversary of the sport.