While his predecessor Ernesto Valverde won two La Liga titles in two years and has the team top once again at the halfway point this season, Setien, apart from some success in Spain's third tier in 2011, has no coaching honours to his name.
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His best La Liga finish was as Real Betis coach in 2018, taking them to sixth and qualifying for the Europa League, but he parted ways with them last season as the team ended up 10th.
The former Racing Santander and Atletico Madrid midfielder's tactical nous was lost at the helm of Betis, with fans turning against him despite the attacking possession football he played, seeking more passion and less precision.
However, in a stylistic sense at least, Setien should fit in perfectly at Barcelona having been inspired by Johan Cruyff's side while playing against them in the late 1980s.
"I remember when Johan Cruyff's Barcelona came along," Setien told The Coach's Voice. "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."
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After the Pep Guardiola and Tito Vilanova era, Barcelona began to lose some of their swagger while still picking up trophies at an impressive rate.
Under Luis Enrique and then Valverde the focus shifted from teamwork to the individual, with elite players such as Lionel Messi and Luis Suarez becoming increasingly important.
Setien, a chess enthusiast who had often been linked with the Barcelona job in the past, must rearrange the pieces to give the Catalans their identity back.
As Valverde discovered, domestic silverware is not enough at Barcelona. Fans demand Champions League success as well as quality performances.
Setien delivered an example of what his sides are capable of last season when Betis beat Barcelona 4-3 at Camp Nou -- the first team in two years to triumph there and also the last side to do so. If that was the coach's job interview, he passed.
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