Clyne made his debut for Crystal Palace in a league fixture on 18 October 2008 against Barnsley. He signed a three-year contract with Palace on 20 October 2008, and Neil Warnock stated Clyne "has a bright future in the game". His first career goal came in a 4–2 win at Reading on 8 December 2009. In February 2010 he was offered a move to Premier League side Wolverhampton Wanderers, but rejected it without even entering talks with manager Mick McCarthy.
In the 2010–11 season, Clyne was the youngest player in the Football League to play every single game of that campaign, and won Crystal Palace's Player of the Year award.
Clyne scored in Southampton's first game of the 2014–15 season, a 2–1 defeat against Liverpool at Anfield on 17 August. He scored his second goal of the 2014–15 season on 23 September, with a long-range effort which gave Southampton a 2–1 victory at Arsenal in the League Cup third round.
On 2 October 2014, Clyne was named in the England squad for Euro 2016 qualifiers against San Marino and Estonia later that month. He was an unused substitute in both matches. On 15 November, he made his full international debut in a home qualifier against Slovenia, playing the full 90 minutes of a 3–1 victory.