With both Xavi and Ronald Koeman turning down the chance to take over their former club, the Blaugrana board have turned to Setien following a challenging period for the club under Valverde.
Indeed, despite winning La Liga in his first two seasons at the club, Valverde’s position at Camp Nou had long been under scrutiny after embarrassing Champions League capitulations, against Roma and Liverpool.
Barcelona were initially eager to appoint Xavi as permanent coach to replace Valverde, but the current Al-Sadd manager did not want to take the job immediately, preferring instead to return in the summer.
However, Setien has been given a contract until the end of the 2021-22 season, meaning we are unlikely to see Xavi back at Camp Nou for some time.
The focus now, then, is on Setien, and Goal has everything you need to know about Valverde's surprise successor, his coaching history and more...
Who is Quique Setien?
Having honed his skills playing beach football, Setien became a legend at Racing Santander, where he is known as 'El Maestro', having spent 12 seasons across two different spells with his hometown club.
He went on to have fruitful spells at the likes of Atletico Madrid and Logrones before retiring after a short stint at Levante, in 1996.
Unsurprisingly, Setien got his coaching career up and running at his beloved Racing, in 2000. Spells at Poli Ejido and Logrones followed before he took charge of the Equatorial Guinea national side for three months. He also trained Lugo for five years, with promotion to Segunda Division B the undoubted highlight of his tenure.
In October 2015, the Spaniard then took on the reins of Las Palmas, who were in the Liga relegation zone at the time of his arrival. Setien eventually led the tiny Canary Islands club to an 11th-placed finish and even had them competing for a European place the following year.
Las Palmas eventually fell short but, by that point, Setien had drawn widespread praise for his side's attractive, possession-orientated football.
It came as no surprise, then, when he was offered the chance to take charge of Betis in 2017.
In his first season at the Benito Villamarin, he secured qualification to the Europa League by finishing sixth in La Liga, with his popularity among the fans having been boosted by a thrilling 5-3 derby win over Sevilla.
Setien's side became synonymous with such results, even beating Barcelona 4-3 at Camp Nou in November 2018 – the Catalan club's last home defeat.
However, he parted company with Betis in the summer of 2019 after a disappointing 10th-placed finish in the Primera Division. The Andalusians had been challenging for a Champions League spot but a steady decline in results led to Setien leaving the club despite having a year left on his contract.
He is fondly remembered by the fans, though, having championed an offensive brand of football and also brought through the likes of Fabian Ruiz, who went on to join Napoli, and current Barcelona left-back Junior Firpo.
A chess fanatic who has even played against world champions Anatoli Karpov and Gary Kasparov, Setien believes some of the game's principles can be applied to football.
He usually favours an attacking 4-2-3-1 formation but his primary obsession is possession.
"Sometimes you see players who can suddenly perform and you think: 'Holy sh*t, where did that come from?'
"You wonder how they're suddenly so good. And it's because you give them something they like: the ball."
Hardly surprising, then, that Barca grew to become such avid admirers of Setien and his style of play.
Sergio Busquets will certainly be looking forward to working with his new boss, having once presented Setien with a signed shirt that read, "For Quique, with love and admiration for your way of looking at football. All the best."
Setien, for his part, makes no attempt to hide his love of the footballing philosophy of the most influential man in the history of Barcelona, Johan Cruyff.
"I remember when Johan Cruyff’s Barcelona came along,” Setien told The Coaches' Voice in 2019.
"You played against them, and you spent the whole match running after the ball. I said to myself: ‘This is what I like. I would like to be in this team, and know why this is happening.’
"How can you get a team to have the ball permanently, so that the opponent is running after it for the whole match?
"From then on, I started to make sense of what I had felt throughout life, through my career.
"I started to really watch football. To analyse it. To understand what I felt, and what I wanted to put into practice when I became a coach."
And now, in a sudden twist of fate, he has been given the challenge of being appointed coach of the club where his style of play was born.