The 42-year-old has signed a three-year deal having just won a third-straight Swiss league title with Young Boys Bern and replaces caretaker coach Hannes Wolf.
"In the professional and ambitious environment at Bayer, I see ideal conditions to play attractive football and to be among the top teams in the league and in Europe," said Seoane in a statement.
He led Bern to the last 16 of the Europa League this season, securing home and away wins over Leverkusen in the first knock-out round.
The German club has reportedly used a release clause in Seoane's Bern contract to sign him for one million euros ($1.2 million).
Since joining Bern in 2018, Seoane has steered them to three Swiss league titles and with one game left, they are 28 points clear at the top of the table.
The son of Spanish immigrants, Seoane was born in Lucerne and made 227 appearances in the Swiss league after a spell in Spain at Deportivo La Coruna as a teenager.
Communication is his strength and as well as German and Spanish, Seoane speaks fluent French, English, Italian and Portuguese.
With one Bundesliga round left, Leverkusen are sixth in the table and on course to play in the Europa League next season.