The club were thrashed 8-0 by champions Bayern Munich in their season opener last weekend and suffered a 3-1 defeat by Werder Bremen on Saturday.
"FC Schalke 04 have relieved David #Wagner of his duties with immediate effect," Schalke said in a tweet.
Schalke are now without a win in their last 18 consecutive league games.
The 48-year-old Wagner joined Schalke in 2019 and in the first half of last season lived up to fans' expectations, with the club in Champions League contention, seven points off the top and with only three defeats in 17 games.
They added only 10 more from their next 17 matches to end up 12th, eight points above the relegation playoff spot.
Schalke said that they would appoint Wagner's successor in the coming days.
