It's the first time the collection has not featured on the chart since its release in January 2011, when it debuted at number one with sales of 200,000 copies.
However, this past weekend saw 21 fall to 42 after 22 months on the list, according to the Official Charts Company.
The album has been certified 15-times platinum by the British Phonographic Industry for sales of more than 4.5 million units.
21 holds the title for the most downloaded album in UK history, as well as the best-selling album in the UK of the 21st century so far. It's also the fifth best-selling album in UK chart history.
Watch the music video for Adele's 'Rolling In The Deep' below: