After 25 years with Real Madrid, Casillas joined FC Porto in 2015 on a free transfer, where he won the Primeira Liga and a Supertaça Cândido de Oliveira title.

In starting the 1999–2000 UEFA Champions League group stage fixture against Olympiakos on 15 September 1999, he became the youngest goalkeeper ever to feature in the competition at the time, aged 18 years and 177 days; a record which was only broken in October 2017 by Mile Svilar.

During the 2009–10 season on 4 October in a game against Sevilla, Casillas made an extraordinary save, running from one side of his goal to the other to deny Diego Perotti in a one-on-one, close-range encounter.

This generated a shift in the opinion of certain sectors of Real Madrid's fans, who gave Casillas the nickname "topor" (a portmanteau of "topo", and "portero", Spanish for "mole" and "goalkeeper", respectively).

He made his first start in 238 days in the Champions League group stage match against Galatasaray, but was injured in the 14th minute after Sergio Ramos caught him with an accidental elbow as the goalkeeper came from his line to make a routine catch.

Although Diego Godín's opening goal resulted from an error by Casillas, Sergio Ramos tied the match for Real Madrid in injury time; the club went on to win the title in extra-time.

After much speculation about his future, on 11 July 2015 Casillas signed with Portuguese Primeira Liga side Porto on a two-year deal with the option of a one-year extension.

[42][43][44] Real Madrid's conduct in his exit was criticised, with Casillas' parents claiming that he was being forced out of the club by president Florentino Pérez, who received calls to quit from fans.

Former international teammate Xavi, who earlier that summer left Barcelona after a similarly long and successful career, claimed that Real Madrid were ungrateful of Casillas' service to the club.

[45] Casillas made his Primeira Liga debut on 15 August, keeping a clean sheet in a 3–0 win over Vitória de Guimarães at the Estádio do Dragão.

[52] On 13 September, Casillas equalled Ryan Giggs's record of playing in 19 consecutive UEFA Champions League campaigns when he appeared in Porto's 3–1 home defeat to Beşiktaş in the 2017–18 edition of the tournament.

[66] In September, he shared the results of his medical tests on social media;[67] at the end of the month, he stated that he would wait until March of the following year to see how he is progressing with his recovery before deciding whether to return to playing or retire.

He played an instrumental role in Spanish progression when he saved a penalty in regulation time and two more in the 3–2 shoot-out victory during the round of 16 match against the Republic of Ireland (1–1 after 120 minutes), earning him the nickname "The Saint".

Casillas saved two penalties from Antonio Di Natale and Daniele De Rossi as Spain eliminated Italy in the quarter-finals with a 4–2 shootout win following a goalless draw on 22 June.

Casillas was the highest-ranked goalkeeper (fourth place) in the 2008 Ballon d'Or, behind Cristiano Ronaldo, Lionel Messi and national teammate Fernando Torres.

[84] Two months later, Casillas made his 100th appearance for Spain in its friendly win over Argentina, making him only the third player in history of Spanish football to ever reach this far internationally.

[86][88] In the course of the finals in South Africa, he kept a joint–record five clean sheets – including in all four games in the knock-out stages –,[86] only conceded a joint–record two goals, and saved a penalty in regulation time in the quarter-final victory against Paraguay.

[95] Casillas then continued his new record unbeaten streak with Spain to 817 minutes, until it was finally broken by Olivier Giroud's injury-time goal on 16 October of that year, which came in a 1–1 home draw against France in a 2014 World Cup qualifying match.

[100] In the team's opening match, he made two mistakes leading to goals from Stefan de Vrij and Robin van Persie as the champions were defeated 5–1 by the Netherlands.

[103] He received criticism for his role in Chile's second goal, where he punched Alexis Sánchez's free kick into the path of the goalscorer Charles Aránguiz.

On 5 September 2015, Casillas kept a clean sheet in his 100th game as Spain's captain, a 2–0 Euro 2016 qualifying win over Slovakia at the Estadio Carlos Tartiere in Oviedo.

[106] On 13 November, Casillas kept his 100th international clean sheet with Spain in a 2–0 friendly win over England, in Alicante, becoming the first goalkeeper ever – male or female – to reach this landmark.

[109] The following day, he became the most-capped European player by earning his 167th cap in a 6–1 friendly win over South Korea in Salzburg in a pre-tournament warm-up match; he was later replaced by debutant Sergio Rico in the second half.

In his prime, he was a spectacular, well-rounded, and athletic keeper, who was known in particular for his outstanding agility, reflexes, consistency and shot-stopping, as well as his foot-work, positioning between the posts, concentration, and speed when rushing off his line in one on one situations;[13][117][121][122][123][124][125][126] he has also stood out for his penalty-saving abilities.

[127][128] In spite of his reserved character, he has been highly regarded for his strong personality, calm composure under pressure, ability to organise his defence, and leadership from the back throughout his career, as well as his reading of the game.

[131][132] He was also known for his ability to save the ball with his feet, with former goalkeeper Manuel Almunia likening him to compatriot Luis Arconada, who also served as an inspiration to Casillas, and to whom he was often compared throughout his career, due to his quick reactions, movement, and excellent footwork.

[136] A precocious talent in his youth, Casillas has drawn praise for his longevity and consistency at the top level,[116][117][121][124] as well as his discipline in training;[92] despite his reputation and goalkeeping ability, however, due to his lack of notable height and strong physical attributes, he has been criticised at times by pundits for struggling to command his area, in particular against aerial threats, and for his unsteady handling and indecisiveness when coming out to claim crosses, as he often preferred to punch the ball away.

He also received criticism in the media for a series of errors and less consistent performances in his later career, as he lost some of his speed and mobility with age due to his physical decline.

In February 2005, Casillas was the football face of Reebok's "I Am What I Am" global integrated advertising campaign that linked all the brand's marketing efforts under one umbrella.

[62][150] Later that evening, Casillas, whose situation had improved, published a statement on Twitter with a picture of himself giving the thumbs up signal in which he thanked the people for the moral support they gave him.