Tziolis began his playing career as a teenager in a local team called Apollon Litochorou. He played there for about seven years and in 1995, a Panionios scouter spotted his talent and brought him to Athens. He was an integral part of Panionios team for three seasons, playing 61 matches and scoring three goals. As a result, Panathinaikos offered Panionios €650,000 and signed him.

After representing his country 13 times for the under-21 side, Tziolis made his international debut for Greece on 21 January 2006 in a friendly match against South Korea. He was a part of the defending European champions at UEFA Euro 2008, where he played once, when he came on as a substitute in a 1–2 loss to Spain in the group-stage. He also made four appearances in qualifying, including as a substitute in the play-off win away to Ukraine.

Tziolis initially established himself as a first-team player for Panathinaikos ahead of Igor Biscan during the 2006–07 season. In April 2007, he scored a goal helping his club break Skoda Xanthi’s unbeaten home run in the Superleague Greece and secure a place in the Greek Cup final against Larissa.

On 7 January 2009, joined Bundesliga side Werder Bremen on a half-season loan, for a fee of €300,000. Werder Bremen secured the right to sign him permanently for a fee of €1.6 million.

Tziolis played a regular role in Bremen’s midfield and helped the club to make the UEFA Cup final against Shaktar Donetsk, on 20 May 2009. In the final, he came on as a substitute for Peter Niemeyer in the 103rd minute. After having nearly scored the equalizing goal when Bremen were a goal behind, the team lost the final of the last UEFA Cup edition to Shaktar with a final score of 2–1. Tziolis also featured in Bremen’s 1–0 victory over Bayer Leverkusen in the German Cup final the same season, where Tziolis won his first ever trophy in professional football.

On 29 January 2010, Serie A club AC Siena, coached by former Panathinaikos coach Alberto Malesani, signed Tziolis for a fee of €1.4 million. He made his debut in the Serie A on 7 February 2010 against Sampdoria. Tziolis was a regular for Siena, while the team was relegated to the Serie B.

In August 2010, Tziolis moved to La Liga side Racing Santander on a one-year loan deal. In October 2010, he suffered a leg break in his nation’s 1–0 win over Latvia and Racing Santander announced that the period of recuperation would be between four and six months.

He was also part of the squad that participated to the 2010 FIFA World Cup. He played every minute of the tournament for his country, including their first ever World Cup win over Nigeria on 17 June 2010.

In January 2012, Tziolis joined Monaco for a reported transfer fee of €200,000.

On 31 August 2012, Tziolis joined Cypriot side APOEL on a season-long loan deal from AS Monaco.

On 25 June 2013, Tziolis signed a three-year contract with Greek Superleague side PAOK. On 17 August, he made his league debut in a 3–0 home win against Xanthi. On 22 December 2013, he scored his first goal with the club in a home victory against Levadiakos. He was among the key players of PAOK in the first half of the 2013–14 season. In the winter transfer window he signed with Süper Lig team Kayserispor with the stated intention of securing his selection for the Greek national team at the 2014 World Cup.

On 31 January 2014, Tziolis signed a six-month loan contract with Kayserispor with Kayserispor being given the option to sign him permanently for a fee of €1.5 million, Nine days later, he made his debut in the Süper Lig in an away loss against Elazigspor.

At the beginning of 2014–15 season, Tziolis returned to PAOK, playing 34 games in all competitions scoring only one goal in the Greek Cup. On 27 November 2015, in the UEFA Europa League match against Gabala FK, Tziolis reached 400 appearances with all his clubs for all competitions.

Tziolis’ contract with PAOK was scheduled to expire at the end of 2015–16 season, but would have been automatically renewed if he had played at least 70% of team’s matches. In December 2015 the club stated it wanted to keep the international midfielder for many years and that Tziolis had had a first meeting with technical director Frank Arnesen, to speak about the terms of a contract extension. On 19 August 2016, PAOK officially announced that the international midfielder was not in club’s plans for the 2016–17 season.

On 28 January 2017, it was announced that his contract with PAOK had been terminated. He left the club having made 111 appearances (four goals, five assists) in all competitions.

On 30 January 2017, Tziollis joined Scottish Premiership club, Heart of Midlothian on a six-month deal running to the end of the 2016–17 season. and made his Hearts debut in the 4–1 win against Rangers. On 4 February 2017, Tziolis scored his first goal as Ian Cathro’s side beat 10-man Motherwell 3–0 at Fir Park. At the end of the season, he was released by the club.

On 4 August 2017, Tziolis signed a two-year contract with newly promoted Saudi Professional League club Al-Fayha FC. On 23 November 2017, he scored his first goal with the club in a 3–1 home win game against Al-Shabab FC. On 2 July 2019, Tziolis departs Al-Fayha after a two-year stay with the Saudi club. Al-Fayha FC did not offer Tziolis a new contract. The 34-year-old joined the Al-Fayha in 2017 and made 58 appearances across all competitions with three registered goals and assists. On 30 August 2019, he terminated his contract with the club.