Škrtel debuted for the Slovak senior team 2004 and has earned a total of 104 caps, making him the third most-capped player of his country at the time of his retirement in 2019, behind Marek Hamšík and Miroslav Karhan.

[5] Škrtel started his professional career at local side FC Baník Prievidza and soon won a move to FK AS Trenčín, where he played 44 games and scored 8 goals for them between 2001 and 2004.

[9] Valencia, Tottenham Hotspur, Everton and Newcastle United were all reported to be interested in his services,[10] but he ended up signing for Liverpool in the January 2008 transfer window.

He put in a number of strong performances with defensive partner Jamie Carragher against many top teams, notably Manchester United, Everton and Marseille in the UEFA Champions League.

On 5 October 2008, Škrtel suffered a serious knee injury after falling awkwardly when challenging Ched Evans late in a game against Manchester City which Liverpool went on to win 3–2.

[20] On 26 February 2010, it was confirmed that he had broken his metatarsal in his right foot while playing in the 3–1 UEFA Europa League victory over Unirea Urziceni the previous day.

[25] On 27 August 2011, Škrtel scored a headed goal for Liverpool against Bolton Wanderers in his first league appearance of the season from an unfamiliar right-back position.

His first goal of 2012 came in a FA Cup fifth round tie against Brighton & Hove Albion, opening the scoring within five minutes of kick-off with header from a corner kick.

[29] On 10 April 2012, Škrtel captained Liverpool for the first time in the league, leading his club to a 3–2 win over Blackburn Rovers and playing a major part in the first goal with a long pass to Craig Bellamy, who subsequently squared for Maxi Rodríguez to make the score 1–0.

[36] After missing the first two matches of the season, Škrtel helped Liverpool keep a clean sheet in 1–0 home win against Manchester United on 1 September.

[42] After a poor beginning to the season, manager Brendan Rodgers switched to a three-man defensive line in October, with Škrtel playing a crucial part.

[45] On 8 March 2015 in a sixth round FA Cup match against Blackburn Rovers, Škrtel was substituted and then taken to hospital after a collision with Rudy Gestede.

[46] Later that month, Škrtel was given a three-match ban for violent conduct by the FA for a stamp on Manchester United goalkeeper David de Gea.

[51] On 6 December 2015, Škrtel joined his former defence partner Jamie Carragher in second position on the All Time Premier League Own Goals list by scoring his seventh in a match against Newcastle.

[56] During autumn 2018 and spring of 2019, Škrtel was linked to transfers to Barcelona that he allegedly turned down on the basis of his potential position in the squad, as well as a lucrative offer of Al-Ahli Jeddah.

Instead, it was stated that he may join his national team teammate Juraj Kucka, prior to Škrtel's international retirement in February 2019,[57] in Parma.

He was the only scorer in club history aged over 37 – precisely 37 years, 2 months and 14 days, beating the previous record held by Karol Tibenský [cs].

[66] In August 2022, Škrtel left Spartak Trnava to fulfil his promise and finish his career at his childhood club FK Hajskala Ráztočno playing a local league in Prievidza.

[citation needed] On 13 October 2018, Škrtel earned his 100th cap in a home friendly match against Czech Republic in Trnava, becoming the third most-capped Slovak footballer.

[70] On 22 February 2019, Škrtel announced his retirement from international football at the age of 34, along with another national team defender Tomáš Hubočan and forward Adam Nemec.

[71] The trio shared a farewell game on 13 October 2019 in a friendly match against Paraguay, which coincided with a national team return to Tehelné pole after 10 years.