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A 1-0 loss at Arminia Bielefeld confirmed a fourth relegation in Schalke's history after three decades in Germany's top flight.
Schalke played the last 19 minutes with 10 men after defender Malick Thiaw was sent off for a second yellow card.
Bielefeld captain Fabian Klos scored the winner early in the second-half to condemn Schalke to their first relegation since 1988 before coming back up in 1991/92.
It is almost exactly 10 years since Schalke's run to the last four of the Champions League.
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Spanish legend Raul scored in a 5–2 first-leg romp at Inter Milan's San Siro in the quarter-finals, before the German club was knocked out by Manchester United in the semi-finals.
The Royal Blues also lifted the German Cup in 2010/11 as Klaas-Jan Huntelaar, who returned to Schalke this January from Ajax, scored twice in a 5-0 thrashing of Duisburg in the Berlin final.
However a decade later, Schalke have won just two of their league games this season and started the season with a record 8-0 thrashing at Bayern Munich.
Only a 4-0 home win against Hoffenheim in January saw Schalke avoid equalling the Bundesliga's record of 31 consecutive games without a win.
The Royal Blues have gone through five coaches this season.
David Wagner, Manuel Baum and Christian Gross were all sacked while Huub Stevens also briefly took charge as caretaker coach in December.
Under current coach Dimitrios Grammozis, Schalke has lost five, drawn one and won one of his seven games in charge.
Schalke heads into the second division saddled with 217 million euros ($261 million) of debt after posting a loss of 52 million euros in the last financial year due to the Covid-19 pandemic.
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