Born on 18 June 1983, Smith attended Marsden State High School.
Smith played at hooker for the Logan Brothers in Logan City. After scoring 188 points for the Norths Devils in the Queensland Cup he moved up to the NRL with the Melbourne Storm club.
Smith's first two games for Melbourne were during the 2002 NRL season, both played at half-back. The following year he played as the Storm's hooker. In 2003 the Queensland rugby league team were without a specialist hooker. After experimenting with different players in the position for the first two matches of the 2003 State of Origin series and losing both, Smith was named at hooker for the third match. For the next six years no other player would wear the number 9 for the Maroons until this run of 19 consecutive Origins was cut due to injury. He was named the Melbourne Storm's rookie of the year in 2003.
In 2005, Smith was named the Melbourne Storm's player of the year. The following year he first represented Australia and won the Dally M Medal. In addition he was again named the Storm's player of the year. Smith led the storm to the 2006 NRL Grand Final. While the game was still in the balance he was forced from the field with injury, which the Storm's loss has been largely attributed to.
Smith was selected to play for the Australian national team at hooker the 2007 ANZAC Test match victory against New Zealand. For the 2007 State of Origin series, Smith took out both the Wally Lewis Medal for player of the series and Ron Mcauliffe Medal for Queensland player of the series. He was also named the Melbourne Storm player of the year. Smith captained the Melbourne Storm in their 34–8 victory over the Manly-Warringah Sea Eagles in the 2007 NRL Grand Final.
Smith became regular captain of the Melbourne Storm in 2008. Smith captained the Maroons for the entire 2008 State of Origin series due to the absence of regular captain Darren Lockyer. The Maroons won the series with him as the skipper, despite losing the first match 18–10. In August 2008, Smith was named in the preliminary 46-man Kangaroos squad for the 2008 Rugby League World Cup, and in October 2008 he was selected in the final 24-man Australia squad. Cameron was suspended for two weeks in the 2008 finals series after a grapple tackle on Brisbane's Sam Thaiday. The suspension would have only been one week had he not have carried over points from a previous grapple tackle in round 1 of the year's competition. This meant he was suspended for Melbourne's 2008 grand final. Melbourne Storm CEO Brian Waldron and coach Craig Bellamy claimed the judiciary had made their minds up before Cameron's case was heard. The judiciary panel members then threatened to sue the club if the comments were not retracted. Cameron signed a four-year extension to his contract in December 2008, resulting in him being a contracted player through to the end of at least the 2012 season. His contract is rumoured to be partly funded by third party sponsors who do not contribute to the standard salary cap. He became the Melbourne Storm's most experienced playing player due to the retirement of Matt Geyer at the end of 2008. He became the last current Storm player in the squad who played under Mark Murray as well as the only one to have played in a season when the Storm did not make the finals due to their performance (the Storm finished 10th in 2002, the year Smith made his debut).
In April 2009, he was named in the preliminary 25 man squad to represent Queensland in the opening State of Origin match for 2009. He was selected for Australia in the one-off test match against New Zealand on 8 May 2009. In the preliminary final in which Melbourne defeated the Brisbane Broncos 40–10, he became Storm's highest ever point scorer, beating Matt Orford's record of 877. Smith led the Storm in their 2009 NRL Grand Final victory over the Parramatta Eels. At the end of the season, he joined the Kangaroos on their campaign to win the 2009 Four Nations tournament in England. He scored the try that saved Australia from losing in the opening match and also scored in the Kangaroos' victory against England in the final.
In 2010 he played in the 2010 World Club Challenge at halfback in the absence of his usual number 7 Cooper Cronk due to injury. Smith kicked 5 goals and was named man of match. For the 2010 ANZAC Test, Smith was selected to play for Australia at hooker in their victory against New Zealand. For the first time since Game II of the 2003 Origin series, Smith wasn't wearing the number 9 for Queensland, after he failed to overcome the elbow injury he sustained playing in that test. He was replaced by Matt Ballin. In Round 26 of the 2010 NRL season Smith became the first Melbourne Storm player to reach 1,000 points after successfully converting Ryan Hinchcliffe's try. Smith played in the 42–0 thrashing of the Papua New Guinea national rugby league team during the 2010 Four Nations. It was a game where he converted 5 tries and scored once. He was later named man of the match.
Smith was named man-of-the-match in Queensland's win in Game I and later Game III of the 2011 State of Origin series, subsequently resulting in his naming as the Wally Lewis medal winning man-of-the-series. On 3 November 2011 The annual RLIF Awards dinner was held at the Tower of London and Smith was named hooker of the year.
Following Darren Lockyer's retirement at the end of the 2011 season, Smith became captain of both Australia and Queensland. He captained both sides to the 2012 ANZAC Test and 2012 State of Origin series victories respectively. At the 2012 Dally M Awards Smith was named the NRL's hooker of the year. He captained Storm to victory in the 2012 NRL Grand Final over the Canterbury-Bankstown Bulldogs. Smith also received the Rugby League International Federation's international player of the year award for 2012.
He then captained them to victory in the 2013 World Club Challenge over Leeds earning the title of world champions. Smith captained Australia in the 2013 ANZAC Test and played at hooker. He kicked four goals from six attempts in what was the first test match ever played in Canberra. After victory in the third and deciding game of the 2013 State of Origin series Smith was awarded the Wally Lewis Medal for player of the series, in which he captained the Queensland team which extended their record winning streak to 8 years.
On 9 June 2013, Smith played his 250th game for the Melbourne Storm, the second only player to have achieved that feat.
Queensland's win in Game III of the 2014 State of Origin series made Smith the first player in State of Origin history to win 20 games.
On 30 November 2013, Smith captained Australia to a dominant 34 to 2 win against New Zealand in the 2013 Rugby League World Cup Final ensuring the Australian side went through the entire tournament undefeated.
In November 2014, in the Four Nations game against England, Smith became just the sixth player to appear for Australia in 40 test matches.
On 9 July 2015, Smith captained Queensland to a 2 to 1 series win against New South Wales winning game three emphatically by 52 – 6. It was Smiths' 9th series win in ten years and his fourth series win as captain. At series end, Smith had equalled Darren Lockyer for most Queensland appearances with 36 and received his fifth man of the match award in game one to sit in equal second behind Wally Lewis for most man of the match awards in State of Origin.
On 17 July 2015, Smith became the Melbourne Storms' first 300-game player and only the 24th player in the history of the NRL to achieve such a feat. As of April 2017, Smith is one of only three current NRL players to have eclipsed 300 NRL games.
On 22 June 2016, Smith captained Queensland to their 10th series win in 11 years over New South Wales. Smith was awarded his sixth man of the match award in game 2 of Origin and was awarded the Wally Lewis medal as the player of the series for the fourth time at series end.
On 10 March 2017, Smith reached 2000 career points in a match against the New Zealand Warriors, becoming the first forward, the first Queenslander, and just the fifth player in history to have achieved the milestone.
On 30 July 2017, Smith became only the 3rd player in NRL history to play 350 games, behind Darren Lockyer (355) and equal with Terry Lamb. On 9th September, he played his 356th match and thereby became NRL's most capped player of all time.