Chambers played for Melbourne in the 2009 NRL Grand Final win against the Parramatta Eels. This was later stripped due to salary cap breaches by the Melbourne Storm.

Chambers switched to rugby union from 2010 after signing a 2-year deal with the Queensland Reds to play in the Super 14. However, following a disappointing 2011 season – where he only started six of the Reds’ 18 matches – Chambers was released by the club after missing a place in their thirty-man 2012 squad. He was named on the bench for the Reds Super 15 final victory over the Crusaders in 2011 – which featured fellow league-turned-union player Sonny Bill Williams on the opposing side – but did not play in the match.

Chambers signed for Pro12 side and former European Champions Munster in September 2011 on a short-term deal. He arrived to join up with Munster in October 2011. He played for Munster A against Connacht A on 21 October 2011. He made his full Munster debut against Aironi on 28 October 2011. He made his Heineken Cup debut for Munster against Northampton Saints on 12 November 2011. Chambers scored his first try for Munster exactly a week later, in their second Pool One game away to Castres Olympique. He was named in the Munster A team to play Ulster Ravens in the British and Irish Cup on 20 January 2012. This was announced to be Chambers last appearance for Munster, as he was returning to Australia to take up a contract with rugby league team Melbourne Storm. Munster A won the game 9–20, securing a spot in the semi-finals. In his four months with Munster, Chambers made 8 appearances for the senior Munster team, including 3 Heineken Cup caps, and scored 1 try. He also made 3 appearances for Munster A.

By being part of the 2012 NRL Grand Final winning team, Chambers joined Peter Ryan, Brad Thorn and Sonny Bill Williams in winning both NRL and Super Rugby titles (though he did not play in the Super Rugby final). Chambers won his in consecutive years after winning with the Queensland Reds in 2011.

He re-joined the Melbourne Storm in 2012, and played his first game on 25 March 2012 against the Sydney Roosters, in which he scored a try. A successful return was exclaimed by scoring a hat-trick against The Warriors.

In 2013, he played in Melbourne’s World Club Challenge victory over Leeds.

In the 2015 pre season, Chambers captained the Melbourne Storm at the NRL Auckland Nines. He was also selected for the Indigenous All Stars in the 2015 All Stars match at the. Gold Coast.

After a great start to the 2015 NRL season, Chambers became the 800th Australian Kangaroo. He made his test debut in the centres against New Zealand Kiwis in the 2015 Anzac Test at Suncorp Stadium.

In the 2016 NRL season, Chambers was part of the Melbourne side which won the Minor Premiership and reached the grand final against Cronulla-Sutherland but were defeated 14–12 at ANZ Stadium with Chambers scoring a try in the second half of the match.

In the 2017 NRL season, Melbourne again won the Minor Premiership and reached the grand final against North Queensland where they won the match 34–6 at ANZ Stadium.

In the 2018 NRL season, Melbourne finished second on the table and reached the 2018 NRL Grand Final against the Sydney Roosters. Melbourne were defeated 21–6 in the final and Chambers was involved in an incident with Roosters player Latrell Mitchell during the match where Chambers was tackled into touch and then pushed into the advertising board by Mitchell. This was a culmination of a rivalry between the two players which had started earlier in the year during the 2018 State of Origin series.

In the 2019 NRL season, Melbourne won the Minor Premiership after a dominant season but were defeated by the Sydney Roosters at the Sydney Cricket Ground. This would be Chambers final game for Melbourne.