The decision to remove Valverde was confirmed following a board meeting that lasted more than four hours at Camp Nou on Monday afternoon.
Barca are top of La Liga but have won only one of their last five matches. Valverde is the first coach the club has sacked mid-season since Louis van Gaal in 2003.
“FC Barcelona and Ernesto Valverde have reached an agreement to terminate the contract that united both parties,” read a club statement released on Monday night.
Setien will be presented in a press conference at Camp Nou at 2.30pm local time (1330 GMT) on Tuesday.
Barcelona and Quique Setien have reached an agreement for the latter to become first team coach until 30 June 2022,” the club said.
“Setien is one of the most experienced coaches in Spanish football,” it added. “Throughout his career he has been a proponent of possession based, attacking football that has been attractive to the fans.”
His first game in charge will be at home to Granada on Sunday. Barcelona play Napoli in the last 16 of the Champions League next month and Real Madrid in the league at the start of March.
Setien has made no secret of his admiration for the stylistic traditions of Barcelona, with the 61-year-old also renowned for favouring an exciting, offensive mode of football.
A former player of Atletico Madrid and Racing Santander, he was circled as a potential Barca coach during a particularly successful period in charge of Real Betis.
Setien led Betis to a sixth-place finish in 2018 and qualification for the Europa League but, despite overseeing a thrilling 4-3 victory at Camp Nou early the following season, results tailed off.
Betis finished 10th and the club and coach parted ways in the summer. Previously, he also helped Las Palmas avoid relegation from La Liga in 2016.
A footballing purist, Setien and Barcelona would seem a good fit, particularly if the players feel released from some of Valverde’s more pragmatic tendencies.
But critics of Setien would argue style often takes precedence over substance and it remains to be seen how he handles the pressure of matching aesthetics with results at one of the world’s most demanding clubs.
He will also have to do without Luis Suarez, who will be missing for the next four months after having surgery on his right knee.
European failures haunt Valverde
Doubts had surrounded Valverde for several months and were underpinned by two disastrous exits from the Champions League.
Barcelona’s shocking collapse against Roma in 2018 was followed by a similar capitulation against Liverpool last year.
Familiar fragility had been evident this season and a 3-2 defeat to Atletico Madrid in the Spanish Super Cup on Thursday, in which Barcelona conceded two late goals, prompted the board to act.
Valverde arrived two hours early for his last training session with the squad at Ciutat Esportiva Joan Gamper on Monday morning before meeting with club president Josep Maria Bartomeu.
Bartomeu then drove to Camp Nou, where he held a board meeting with several club officials including chief executive Oscar Grau, technical secretary Javier Bordas, vice president Jordi Cardoner and sporting director Eric Abidal.
Grau and Abidal had returned to Barcelona on Sunday after spending the weekend in Qatar, where they had offered the job to Xavi, only for the club’s iconic former midfielder to indicate he was not ready to come immediately.
In Valverde’s two seasons, his team won two La Liga titles, as well as the Copa del Rey in 2018, and another league success remained very much in sight this term, despite Madrid’s impressive form in recent weeks.
But Barca’s performances have been unconvincing and there were lingering concerns about Valverde’s more functional tactics, which appear to have informed the switch to Setien.
When Valverde arrived in 2017, Barcelona were wounded, hurting after the shock departure of Neymar to Paris Saint-Germain and humiliated, as consecutive defeats by Real Madrid in the Spanish Super Cup hinted at trouble for the season ahead.
Instead, he steadied the ship and galvanised the team.
They lost one league game en route to winning the title and the year after, they were champions again, finishing 11 points ahead of Atletico and 19 clear of Real.
Increasingly, though, Valverde’s achievements faded from view and his failures began to overshadow them. On Monday, Barcelona decided his time was up