The former West Bromwich Albion boss took over at the Estadio Benito Villamarin in December 2014 for a second stint in charge having previously managed them between February 2010 and December 2013.
However, he has now been sacked for a second time by the club following his side's 1-0 defeat away to Getafe on Saturday.
That result was the fourth loss in a row for Betis in all competitions, a run which has seen them drop to 15th in La Liga, now just five points clear of the relegation zone.
Betis have not won in the league since November and have failed to even score a La Liga goal in their last five outings - a drought that stretches back more than a month to December 5.
"Real Betis appreciate the services rendered to our club by Pepe Mel and wish him well in his future professional endeavours," read a club statement.
Mel steered Betis back into the top flight as Segunda Division champions last season, but picked up only one point from his last five games in charge.