Vrba has activated an exit clause in his contract with the Czech champions and will leave the club on December 15.
He is then poised to take over his national side from January 1, ending the interim stewardship of Josef Pesice, who stepped in when Michal Bilek resigned in September.
Miroslav Pelta, president of the Football Association of Czech Republic (FACR), expressed satisfaction at securing the services of Vrba.
"Of course I am very happy that we get a coach who has had a number of excellent results," said Pelta in a statement on the FACR website.
Vrba guided Plzen to their first domestic title in 2011 and secured a second crown last season.
The 49-year-old's next challenge will be to seal Czech Republic's qualification for the 2016 European Championship.
A statement on Plzen's website confirmed the club had wanted Vrba to stay.
It read: "The use (of the exit) clause is purely a decision (by) Pavel Vrba, who prefers another challenge."
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