Avenging their 2014 Champions League defeat by Real Madrid on Saturday would complete the transformation.
The former Atletico midfielder inherited a team that had just suffered early elimination from the King's Cup when he succeeded Gregorio Manzano in December 2011.
Five months later, Simeone led them to a fifth-place finish in La Liga and lifted the Europa League, the first of five trophies the team would win. Only the Champions League remains.
In 2014, a header by Real Madrid's Sergio Ramos during injury time snatched that prize from Atletico. It is testament to Simeone's management that he has led them to another final two years later.
"Diego Simeone is the perfect coach for Atletico Madrid," said the club's president, Enrique Cerezo, who had overseen 52 managerial changes before appointing the Argentine. "Football is his life and passion."
Cerezo once said he wished Simeone could have the same impact on his club as Alex Ferguson had with Manchester United.
Simeone may still be a long way off Ferguson's 27 seasons at Old Trafford, but he has already carved out his own legacy with Atletico.
With 173 league games under his belt, Simeone is the club's second-longest-serving coach behind the late Luis Aragones.
Halting Real Madrid and Barcelona's decade of dominance in La Liga by leading Atletico to the title in 2014 is his greatest achievement so far.
Masterminding the club's first-ever success in European football's premier competition would surmount that. Victory in Milan would give Simeone a sixth trophy and equal Aragones' record as the club's most successful manager.
Simeone is the longest-serving of all current coaches in La Liga and looks set to continue his stay. He has signed a contract until 2020 and, barring any surprises, will lead the club into La Peineta stadium at the start of the 2017-18 season.
But perhaps Simeone's most impressive achievement has been converting the team to his brand of high-intensity football. Now his players vigorously defend their hard-nosed style.
"We're a group of players who'll fight to the death for our coach," defender Diego Godin said. "We believe in what we do and we train hard to compete with the biggest teams."
"Every ball is a war we have to win, and I don't see that as a bad thing," midfielder Saul Niguez said. "We're a strong team and we fight for every ball like it's our last. That's how we manage the toughest games and that's how we've got to where we are."
