Since becoming an independent nation in 1993, the Central European outfit have only participated in the showpiece in the 2006 edition.
They're now aiming to end the long wait for another appearance in the finals, though Jaroslav Silhavy's side have a fairly tough group to negotiate.
Belgium and Wales are the favorites to advance from Group E but the Czech Republic's strong run in the last few years should make them a dark horse.
They qualified for the 2020 European Championship from their group behind England and then got promoted to Tier A of the UEFA Nations League.
The Czechs will be looking to kick-start their qualifiers with an easy win against minnows Estonia, who're ranked 108 in the world.
The Baltic side often finish bottom of their groups in these qualifiers and haven't won a competitive fixture since March 2019.
Estonia vs Czech Republic Head-To-Head
The sides have clashed only thrice before, with the Czechs winning on all three occasions.
However, their last clash came way back in June 2004, when the Locomotives secured a 2-0 friendly win on home soil.
Estonia Form Guide (all competitions): L-D-D-L-D
Czech Republic Form Guide (all competitions): L-W-L-W-W
Estonia vs Czech Republic Team News
Thomas Haberli has named a fairly young squad featuring Arsenal goalkeeper Karl Jacob Hein, Karol Mets, captain Konstantin Vassilijev and striker Henri Anier.
However, some experienced players such as Siim Luts, Ilja Antonov, Henrik Ojama, and Sergei Zenjov will miss out.
Injured: Siim Luts
Unavailable: Ilja Antonov, Henrik Ojama, and Sergei Zenjov
Silhavy has named a strong squad for the upcoming triple header of matches. The squad features Sevilla goalkeeper Tomas Vaclik, Pavel Kaderabek, West Ham's Tomas Soucek, and Bayer Leverkusen star Patrik Schick.
Petr Sevcik is the only notable absentee for the visitors.
Injured: Petr Sevcik
Estonia vs Czech Republic Predicted XI
Estonia (4-2-3-1): Karl Jakob Hein; Nikita Baranov, Joonas Tamm, Marten Kuusk, Artur Pikk; Vladislav Kreida, Mattias Kait; Sergei Mosnikov, Konstantin Vassilijev, Vlasiy Sinyavskiy; Rauno Sappinen.
Czech Republic (4-2-3-1): Tomas Vaclik; Vladimir Coufal, Pavel Kaderabek, Ales Mateju; Ondrej Kudela; Tomas Soucek, Alex Kral; Lukas Masopust, Vladimir Darida, Jakub Jankto; Patrik Schick.
Estonia vs Czech Republic Prediction
Given Estonia's poor record historically, the Czechs should nick this one without much hassle.
Prediction: Estonia 0-2 Czech Republic