Atletico fell to a 2-1 loss against Sevilla on Saturday night, with their rivals for a spot in the Champions League remaining second in the table.
A stunner from Ivan Rakitic and a late Lucas Ocampos winner left Atleti in the mire, down in fifth, embarrassingly below Madrid minnows Rayo Vallecano.
It turned out to be a historic defeat for Simeone, who has lost three consecutive games for the first time since taking over as manager in 2011. Their previous two defeats came against Mallorca as well as arch-rivals Real Madrid.
Atleti are now 13 points off leaders Real, in an era when they have been out-spending the Spanish giants and their Clasico rivals Barcelona, but have failed to convince.
Simeone already boasted an enviable title-winning forward group of Luis Suarez, Joao Felix and Angel Correa last season, which was added to in the summer by the return of Antoine Griezmann and the purchase of Matheus Cunha.
The club legend is struggling to get to grips with his new squad though, with the league's player of the year last season, Suarez, becoming a problem for his lack of activity outside of the box.
That saw the Uruguayan substituted in the 57th minute against Sevilla with the score 1-1, and his reaction painted a picture.
Reports in Spain claim the former Liverpool and Barcelona striker said "A*******, always the same," as his number was called, and he was then seen looking livid on the bench.
Suarez, though, may have to look at himself, with the formerly unstoppable striker experiencing one of the worst droughts of his career in front of goal.
The 34-year-old has been kept off the scoresheet for the seventh consecutive game, his longest baron run since a streak for Ajax all the way back in 2007.
A legend as a player and manager at the club, Simeone's job will likely never be in question, but there's no doubt the pressure is rising.
"Well I always talk about the reality of my team," the Argentine said post-match. "We know what we're going through is a tough moment where the results aren't going our way.
"I'm still as excited as I was the first day I arrived here as manager, I know you have to keep working hard and try to get people back fit.
"But most importantly we need to rebuild the confidence of the squad because we know that we can turn things around in the next few games and that's the reality that I see.
"We obviously have to look at ourselves and look where we can improve, but I have full confidence in my squad."
The most worrying thing of all though is the defence, with Simeone's sides usually bulletproof at the back.
Only Cadiz have conceded more goals in the final five minutes of league games than Atleti's six, but lead defender Filipe was far less flattering than his manager.
"We have to pay more attention," he said.
"We were on top of our game for the first 15 minutes, but then we suffer from set plays and it's not the first time that it's happened."
Atleti have already conceded 20 goals, only five less from their total last season, and unless things are sorted out quickly, Simeone will have plenty more explaining to do.