Gian Piero Gasperini's men welcome the buoyant Biancocelesti for the first of two meetings between the clubs in the space of four days, having just taken maximum points from league leaders AC Milan.
Unable to get their hands on the famous old trophy since 1963, Atalanta come into this year's last eight of the Coppa Italia as one of the favourites to claim glory in May.
La Dea's merited 3-0 defeat of Milan on Saturday evening was just the latest in a string of dominant showings from the Bergamo-based outfit, who are level on points with Juventus and just one behind third-placed Roma in the Serie A standings.
Re-established as a team to fear, Gasperini's men have now suffered just a single defeat in 13 matches in all competitions, and they clearly made the short trip to Milan with the intent to derail their more illustrious local rivals. Second-half goals from key forwards Josip Ilicic and Duvan Zapata sealed the deal at San Siro and the pair will again be integral to the side's efforts against Lazio.
The last meeting between the two teams took place at the end of September, ending 4-1 to the Bergamaschi - largely thanks to the inspired interventions of then-captain Papu Gomez.
Since the playmaker's removal from the squad due to an irreparable fall-out with Gasperini - which many thought would leave an unfillable void - recent stats to emerge in the Italian media show that Atalanta have established an even better record without him on the pitch.
Having averaged 1.5 points per game with Gomez and 2.3 without him so far, they also have improved in terms of both goals scored and goals conceded by around a goal per game.
Such a situation indirectly highlights the Nerazzurri's growing squad depth this year - demonstrated by a much-changed XI seeing off Cagliari with ease in the previous round - but Gasperini's selection this time out will likely be much closer to his first-choice side.
Lazio are currently seventh in Serie A - just two points behind their hosts this week - and have finally found form after a disappointing start to their 2020-21 season.
Strikes from goalscoring stalwarts Ciro Immobile and Sergej Milinkovic-Savic saw the Biancocelesti to a 2-1 win over fellow top-four contenders Sassuolo at the weekend - an impressive come-from-behind victory.
Clearly galvanised by beating rivals Roma 3-0 in the Derby - amid a five-match run of successes which has seen the Biancocelesti gain ground on their fellow contestants for a European spot and knock Parma out in the last 16 of the cup - Simone Inzaghi's men remain undefeated this calendar year.
Integral to the improvement of a previously inconsistent side has been a greater resilience in defence. After conceding 25 goals in their first 16 games, Lazio have now let in just four more goals in their last six outings.
Having reached the final twice in the past four years - last lifting the trophy in 2019 - Lazio have been Coppa Italia specialists in the 21st century; also emerging victorious in 2000, 2004, 2009 and 2013.
With seven wins in all, one of the competition's most successful clubs now continue this year's challenge away to a similarly in-form outfit - in a finely-balanced encounter set to enthrall throughout.
Atalanta BC Coppa Italia form: W
Atalanta BC form (all competitions): WWWDDW
Lazio Coppa Italia form: W
Lazio form (all competitions): DWWWWW
At this advanced stage of the competition, home boss Gian Piero Gasperini is expected to reduce his turnover of personnel. Striker Luis Muriel, goalkeeper Marco Sportiello and new signing Joakim Maehle are considered most likely to come into a settled first XI - for Duvan Zapata, Pierluigi Gollini and Hans Hateboer respectively.
Midfielder Mario Pasalic remains unavailable due to injury, but otherwise Atalanta have a fully fit squad for Lazio's visit, though back-up forward Sam Lammers has been heavily linked with a move away this week.
Lazio have a number of injury issues in attack, as Joaquin Correa had been out for a month before making his comeback last week and star striker Ciro Immobile is unable to train consistently due to an ankle injury. Coach Simone Inzaghi confirmed that both Immobile and fellow forward Felipe Caicedo played with pain-killing injections on Sunday, so Vedat Muriqi could be in line for a call-up.
Influential midfielder Luis Alberto is currently recovering from appendicitis, while Luiz Felipe and Danilo Cataldi are longer-term absentees.
Club captain Senad Lulic may be set for a first start since returning from injury, with Adam Marusic dropping out, while either Correa or Andreas Pereira are favoured to replace Luis Alberto behind the front two.
Atalanta BC possible starting lineup:
Sportiello; Toloi, Romero, Djimsiti; Maehle, De Roon, Freuler, Gosens; Pessina, Ilicic; Muriel
Lazio possible starting lineup:
Reina; Patric, Hoedt, Acerbi; Lazzari, Milinkovic-Savic, Escalante, Pereira, Lulic; Correa, Immobile
We say: Atalanta BC 2-1 Lazio
An abundance of attacking quality could see armchair fans enraptured by these two teams near the top of their form - the first of two consecutive clashes between top coaches Inzaghi and Gasperini.
Atalanta's record against the top sides - including Lazio earlier in the season - is largely positive and they do not fear the big occasion. However, Lazio are well-versed in reaching the Coppa's latter stages and are equally capable of nicking a sixth win on the spin. Only a moment of magic might separate them on Wednesday.