Former Villarreal and Club Brugge coach Garrido takes over at the Benito Villamarin until the end of the season after Mel, whose three-and-a-half-year tenure saw him guide the Seville club from the second division to the Europa League, was sacked with Betis propping up the La Liga table.
A haul of only 10 points for the current domestic campaign - Los Verdiblancos' current streak has seen them lose six times in eight games - convinced the club's board to stand the 50-year-old down.
Garrido is highly regarded in Spain for steering Villarreal into fourth place and the Champions League in 2011.
That year also saw the Yellow Submarine reach the semi-finals of the Europa League, where they were eliminated by eventual winners Porto, under the Valencian's supervision.
A statement published on the club's official website read: "Juan Carlos Garrido is the new coach of Real Betis until the end of the season.
"The Club hope that this decision gives the team the boost it needs to return to winning ways."
Last week saw Betis secure their progression to the knockout stages of the Europa League but Sunday's 2-2 draw at home to 17th-placed Rayo Vallecano meant the Andalusians had won only two league games all season.
"Real Betis, with their sports team in a delicate position and needing to change the dynamic of results, can announce their decision to dispense with the services of Pepe Mel, first-team coach since the summer of 2010," read a club statement.
By May 2011 Mel had won promotion to La Liga for Betis at the first time of asking. A 12th-placed finish was then followed by seventh place and qualification for the Europa League last season.
"The club would like to thank the coach for these years of commitment and dedication, in which he has overseen a project that led Betis out of the Segunda Division and into Europe," the statement added.
"The work of his assistants Roberto Rios and David Gomez is also appreciated."
The emotional coach addressed reporters to express his gratitude for the affection shown to him by fans during his time on the Verdiblanco bench.
Quoted on realbetisbalompie.es, the Madrid-born tactician said: "This is the press conference that I never wanted to hold.
"I want to thank the president (Miguel Guillen) and many other people - I can certainly start by thanking every player Roberto, David and I have worked with since 2010.
"Thanks for all the work you've done with us.
"We've gone through bad times and had to overcome them but now, unfortunately, we could not resolve this situation.
"I would ask you all to show the new coach the same love you showed me. Thanks to everyone."
Garrido's first appointments on the Betis bench see him tackle Lleida and Rijeka - in the Copa del Rey and Europa League respectively - before a league trip to Real Sociedad beckons on December 15.