The Red Bulls were held by Hertha Berlin in midweek and head into the weekend matches nine points off top spot, while Koln are also aiming to respond to a bad result last time out.
Too many draws have ultimately cost Leipzig any chance of challenging Bayern Munich for the title as we head into the final stretch of the campaign.
Julian Nagelsmann's men played out a 2-2 draw with Hertha on Wednesday - their fourth draw in five matches either side of the two-month coronavirus-enforced shutdown.
The nine-point gap on top spot is surely now too big to bridge, but Leipzig still have plenty to play for over their remaining six matches.
Finishing second will be the target for Nagelsmann, though securing a place in the top four to qualify for next season's Champions League will be the immediate priority.
Bayer Leverkusen's 1-0 win over Freiburg on Friday pushed Leipzig down to fourth, two points above Borussia Monchengladbach in what has been a thrilling top-four battle.
The visitors' fate is still in their own hands, but a repeat of the performance against Hertha and they will likely end the gameweek outside the Champions League spots.
Timo Werner scored a hat-trick in last week's 5-0 thrashing of Mainz 05, but three days on from that impressive display Leipzig failed to turn up against Hertha and paid the penalty - quite literally.
The Red Bulls are on a nine-game unbeaten run in the Bundesliga and into the quarter-finals of the Champions League for the first time, but Nagelsmann will surely be concerned about the high number of draws in the second half of the campaign.
That is something they can put right on Monday against an out-of-form Koln side that are without a win in four matches - each of those behind closed doors - which is their longest-such run under Markus Gisdol.
The Billy Goats have slipped down to 11th after collecting two points from the last 12 on offer, but they certainly know where the net is, having scored at least once in each of their last 14 Bundesliga matches.
Koln do not tend to fare well in this fixture, however, with their loss percentage against Leipzig (60%) higher than against any other Bundesliga side they have faced at least twice.
Indeed, Leipzig have lost none of their 14 top-flight matches against promoted sides, a run that includes a 4-1 win on home soil in the reverse fixture with Koln six months ago.
FC Koln's Bundesliga form: WWLDDL
RB Leipzig's Bundesliga form: WDDDWD
RB Leipzig's form (all competitions): DDWDWD
Schick scored a fortunate goal and will likely retain his place alongside Werner, but changes will be required elsewhere.
As for Koln, they will be without Sebastiaan Bornauw after the defender was dismissed in the 3-1 loss to Hoffenheim last time out.
Further up the field, Jhon Cordoba looks certain to lead the Billy Goats' line following a good run of form in front of goal.
FC Koln possible starting lineup:
Horn; Ehizibue, Mere, Leistner, Schmitz; Skhiri, Hector; Kainz, Uth, Jakobs; Cordoba
RB Leipzig possible starting lineup:
Gulacsi; Mukiele, Klostermann, Upamecano, Angelino; Sabitzer, Laimer; Nkunku, Olmo, Werner; Schick
We say: FC Koln 1-2 RB Leipzig
Koln can be happy with their first season back in the Bundesliga, but they have gone off the boil and do not have the best of records against Leipzig. Nagelsmann's men need to start turning draws into wins and we expect that to happen on Monday, with this becoming the first German top-flight fixture to be staged in the month of June for 25 years.