The hosts have won back-to-back matches to climb up to 11th, eight points off a Europa League qualifying berth, while Mainz are still at serious risk of being relegated after failing to win any of their last five league games.
Wednesday's 3-0 win over Werder Bremen was just the second time all season Frankfurt have won successive league games, all but ending any threat of relegation.
Adi Hutter's side are now seeking three wins in a row for the first time in 2019-20, having taken just one point from their previous six matches.
That poor run of form will ultimately cost them any hope of challenging for the top six, though victory this weekend and some favourable results elsewhere - namely Wolfsburg losing to Werder Bremen - could change all that.
However, Frankfurt are without a win in their last three home Bundesliga matches and have won only one of their last eight at Commerzbank-Arena.
Mainz have drawn their last two away games since football resumed in Germany, taking points off FC Koln and Union Berlin, but they are now winless in five games overall.
That is Karnevalsverein's longest wait for victory under Achim Beierlorzer, with their most recent victory coming against bottom side Paderborn in February.
Indeed, with 28 points from 29 matches, Mainz are enduring the second-worst season in their Bundesliga history. Only in 2017-18 have they been worse off at this stage, with 27 points.
Mainz have conceded 62 goals in their 29 matches, which is the joint-worst defensive record alongside Bremen.
Beierlorzer's side remain one point above Fortuna Dusseldorf in the final relegation playoff spot with five games to go, including trips to Borussia Dortmund and Bayer Leverkusen.
Those tough upcoming fixtures make this trip to Frankfurt all the more important for Mainz, whose impressive recent record in this fixture does at least offer them some hope.
The visitors have won their last two league meetings with the Eagles - 2-0 and 2-1 - and have lost just one of the last six encounters.
Frankfurt's Bundesliga form: LLLDWW
Frankfurt's (all competitions): LLLDWW
Mainz's Bundesliga form: WDDLDL
Frankfurt striker Andre Silva has scored in four of five Bundesliga games since the restart and has netted in each of the last three matches.
The AC Milan loanee is almost certain to lead the line for the hosts, then, but changes could be made elsewhere as Bas Dost is pushing for a recall after assisting a goal from the bench last time out.
Up the other end of the pitch, Jean-Philippe Mateta scored 14 goals last season but has just two in 2019-20.
Frankfurt possible starting lineup:
Trapp; Abraham, Hasebe, Hinteregger; Chandler, Ilsanker, Rode, Kostic; Kamada; Dost, Silva
Mainz possible starting lineup:
Muller; Brosinski, Bruma, Niakhate, Martin; Barreiro, Kunde; Awoniyi, Boetius, Quaison; Mateta
We say: Frankfurt 2-0 Mainz
Mainz have failed to win any of their matches since returning to action last month and dropping 12 of the last 15 points on offer. They have the ability to grind out draws on their travels, but Frankfurt are on a high following back-to-back wins and we are backing them to prevail on Saturday.