The Reds travel to the German village, which has a tiny population of approximately 3,300, to face the Bundesliga outfit, who are making their European debut at the Rhein-Neckar-Arena.
Liverpool are looking to reach the group stages for just the second time in eight years, with this game their first in three years in the competition, and they will hope for a crucial advantage to take to Merseyside for the second-leg next week.
It is just the second competitive game of Liverpool's season after Jürgen Klopp's side opened their Premier League campaign with a thrilling 3-3 draw away at Watford on Saturday.
Sub-standard defending - particularly at corners, conceding twice from just three - ultimately cost them victory late on in the game as they were denied a winning start to 2017-18.
Reds facing tricky first-leg in Germany
And it is those weaknesses at the back which Hoffenheim - managed by 30-year-old tactical prodigy Julian Nagelsmann - will look to exploit as they look to cause a huge upset and go to Anfield at the very least on level terms.
The clash represents the biggest game in Hoffenheim's 118-year history, having only been in the Bundesliga since 2008, their rise correlating with the financial backing of billionaire software entrepreneur Dietmar Hopp.
Despite their lack of European experience, Hoffenheim will prove a stern test for Liverpool after finishing fourth in the German first division last term - two points behind third-placed Borussia Dortmund - just a season after they had nearly been relegated.
Although they have lost key players in Niklas Süle and Sebastian Rudy - the duo both moving to rivals Bayern Munich - they remain a dangerous attacking team, particularly given the summer addition of ex-Arsenal winger Serge Gnabry - on loan from Bayern.
The South-West German club also have familiar faces in former Leicester City striker Andrej Kramarić - who netted 18 goals last term - and defender Harvard Nordveit, who only joined from West Ham United in June.
Attacking midfielder Kerem Demirbay and striker Sandro Wagner are among their key players, the pair two of Nagelsmann's chief attacking threats, with Liverpool's back-line facing a tricky evening.
Also solid at the back, Hoffenheim represent the toughest opponents Liverpool could have faced at this stage - although the Premier League side were unbeaten in 10 games against the rest of the English top-flight's top seven last term and appear to relish such encounters.
The two-legged tie is a potentially season-defining clash for Liverpool, whose entire campaign last year was focused upon sealing a return to the competition for the club's benefit on and off of the field.
Having endured a so-far-underwhelming summer and with the possibility of their talisman - Philippe Coutinho - leaving for Barcelona before the end of August, ensuring a return to the Champions League groups is the boost that the club needs and Klopp will look to ensure his side's first-leg performance shows as much.
Nagelsmann has a near full Hoffenheim compliment to choose from, though Ádám Szalai - who scored eight goals in 22 Bundesliga games last season - is out with a calf injury and midfielder Florian Grillitsch is sidelined by a metatarsal issue.
Liverpool are without Philippe Coutinho and Daniel Sturridge due to back and muscle injuries while right-back Nathaniel Clyne remains out after missing all of pre-season.
Ex-Hoffenheim forward Roberto Firmino is expected to start alongside Sadio Mané and Mohamed Salah, all three of whom scored in the club's opening league game at the weekend.
Liverpool's full 22-man squad
Goalkeepers: Simon Mignolet, Loris Karius, Danny Ward.
Defenders: Trent Alexander-Arnold, Alberto Moreno, Dejan Lovren, Joël Matip, Joe Gomez, Ragnar Klavan, Jon Flanagan, Andrew Robertson.
Midfielders: Georginio Wijnaldum, Jordan Henderson, Emre Can, Marko Grujić, James Milner.
Forwards: Sadio Mané, Mohamed Salah, Ryan Kent, Roberto Firmino, Dominic Solanke, Divock Origi.
Watford 3-3 Liverpool (Mané, Firmino penalty, Salah) - Premier League
Rot-Weiss Essen 0-1 Hoffenheim (Amiri) - DFB-Pokal
This is the first ever meeting between these two teams.
The game will be Hoffenheim's European debut, having never taken part in any continental competition before.
Liverpool are unbeaten in their last six meetings in European football with German clubs. Their overall record against German teams reads: W17, D13, L6.
Ex-Dortmund and Mainz boss Jürgen Klopp has faced Hoffenheim 16 times as a manager, winning five, drawing six and losing five.
Liverpool have won just one of their last 12 European away fixtures, drawing six and losing five. Their last win came under Klopp in the Europa League group stages in November 2015.
Hoffenheim went the entire 2016-17 Bundesliga campaign unbeaten at home. Only Bayern and Dortmund (both 43 points) earned more Hoffenheim's tally of 39, having won 11 and drew six home games.
Liverpool forward Firmino scored 38 goals in 140 games for Hoffenheim between 2011 and 2015 before a £29 million move to England.