John was the second son of Henry IV, Duke of Mecklenburg, and his wife Dorothea, daughter of Elector Frederick I of Brandenburg.
His earliest documented official act (jointly with the father) was in 1451.
In 1464 he ruled an apanage of several districts jointly with his brother Albert VI, but did not participate actively in administering them.
In 1472, John VI was engaged to Sophie, the daughter of Duke Eric II of Pomerania.
His last illness was contracted on a journey to Franconia to visit his uncle Elector Albrecht III Achilles of Brandenburg.