As secondary coach and then defensive coordinator, Pagano teamed with the future Hall of Fame linebacker to help the Ravens reach a pair of AFC championship games before taking the Indianapolis Colts' head coaching job in January.
The game plans Pagano put together during those years weren't able to prepare him for what he'd endure next.
Pagano is back on the Colts' sideline after beating leukemia in time for Sunday's wild-card matchup against his former team in Baltimore, which could be the final time Lewis steps between the lines after announcing his decision to retire following the playoffs.
Indianapolis was 1-2 when Pagano took an indefinite leave of absence to receive treatment, beginning a "Chuckstrong" movement that captivated the league.
He stayed close to the team as interim coach Bruce Arians and No. 1 overall draft pick Andrew Luck helped transform Indianapolis from a two-win team in 2011 to a playoff qualifier.
Pagano returned after a 12-game absence and couldn't hide his emotions during the Colts' 28-16 home win over Houston last week that capped an 11-5 regular season, and he's not about to rest as his team prepares for a tough postseason matchup.
"My doc said be prudent, if you remember, but I may not be prudent this week in spending a lot of time in a lot of different areas in trying to get as much information out as I possibly can and help where I can,'' Pagano said.
His knowledge of the Ravens' defense surely will be a benefit for Indianapolis, but it may have to contend with Lewis, who expects to play after missing the last 10 games with a torn right triceps.
The good news of Lewis' possible return, though, took a twist Wednesday as he announced plans to end his 17-year career when Baltimore's season concludes.
Lewis made 13 Pro Bowls and was a seven-time All-Pro while twice being named defensive player of the year. He won a Super Bowl ring following the 2000 season and is the only player in NFL history with at least 40 career sacks and 30 interceptions.
Fourth-seeded Baltimore and No. 6 seed Cincinnati would have to reach the AFC championship for Lewis to play another home game.
"Everything that starts has an end,'' said the 37-year-old Lewis, who plans to spend more time with his sons - including his oldest, Ray III, who will play at Lewis' alma mater of Miami. "For me, today, I told my team that this will be my last ride.''
Pagano, who was conducting his Wednesday press conference as news broke of Lewis' retirement, said the fact he's facing Lewis and the rest of a defense he helped coach in his first playoff test seems fitting.
"Nothing shocks me anymore," Pagano said. "Everything that's transpired to this point, I guess it was just meant to be."
The Ravens are fond of Pagano as well.
"Chuck's like a dad to me,'' safety Ed Reed said. "He means a lot to me. I would have much rather seen them in the AFC championship game than the first game.''
With Peyton Manning under center, the Colts won eight straight meetings - including two playoff victories - before the Ravens (10-6) took the most recent matchup 24-10 on Dec. 11, 2011.
Luck will be the first quarterback other than Manning to start a postseason game for Indianapolis since his former coach at Stanford, Jim Harbaugh - the current San Francisco coach and brother of Baltimore coach John Harbaugh - was under center for the Colts' 42-14 wild-card loss to Pittsburgh in 1996.
Luck has experienced an up-and-down first season, ranking 31st in completion percentage (54.1) and 26th in passer rating (76.5), but he threw five touchdowns without an interception in the Colts' final three games.
Baltimore finished 17th in total defense (350.9 yards per game) - its lowest ranking since the 2002 team finished 22nd - and Luck believes Pagano's knowledge of that unit will be beneficial Sunday.
"They're a great team,'' Luck said. "Obviously, coach Pagano knows more about them than I do so I'll lean on him, but obviously (it's) a historic defense."
The Ravens, though, dropped four of their last five games after falling 23-17 to Cincinnati in Week 17, though Harbaugh rested most of his starters with the division locked up.
Joe Flacco - the only starting QB in NFL history to make the playoffs in each of his first five seasons - attempted only eight passes, and Ray Rice had just three rushing attempts. Receiver Anquan Boldin sat out with a bruised shoulder, though he's expected to play Sunday.
Terrell Suggs (biceps) also didn't play last week but he, Lewis and safety Bernard Pollard, who missed the final three weeks with a rib injury, all hope to be on the field together for the first time this season against the Colts.
"This is the first time we get a chance to get our defense back. We're excited and ready to roll," Pollard told the team's official website.
Harbaugh knows Sunday will be an emotional contest given Lewis' pending retirement and the team's ties to Pagano.
"It will be great. It's something that, in this profession, is a big deal,'' said Harbaugh, the only coach in league history with a postseason win in each of his first four seasons.
"Relationships are important. But by the same token, it's a game and they're the opponent.''