Hostilities were renewed in May 1500, when Ivan III took advantage of a planned Polish–Hungarian campaign against the Ottoman Empire: While preoccupied with the Ottomans, Poland and Hungary would not assist Lithuania. The pretext was the alleged religious intolerance toward the Orthodox in the Lithuanian court. Helena was forbidden by her father Ivan III to convert to Catholicism, which provided numerous opportunities for Ivan III, as the defender of all Orthodox, to interfere in Lithuanian affairs and rally Orthodox believers.

The skilled Russian commander employed similar tactics that proved successful for the Russian army in the Battle of Kulikovo. Vedrosha was a crushing victory for the Russians. Some 8,000 Lithuanians were killed, and many more were taken prisoner, including Prince Konstantin Ostrogski, the first ever Grand Hetman of Lithuania. After the battle the Lithuanians lost the possibility for military initiative and restricted themselves to defensive actions.