Roque, who came through the youth ranks at Liverpool before returning to his homeland with Betis, underwent surgery to remove a tumour in his pelvis last year.
"The Real Betis player Miquel Roque Farrero, Miki Roque, has died today at the Instituto Dexeus de Barcelona hospital at the age of 23," a statement on Betis' official website read.
"Miki Roque had been battling pelvic cancer since March 2011, a struggle that he fought with fortitude and determination.
"The board of directors, the technical staff, the first team and the youth ranks, as well as the most important section of the club, the fans, are united in the tremendous pain felt at the passing of a young footballer, of one of our own."
"Real Betis send their deepest condolences to the Roque family."
Roque spent four years at Liverpool between 2005 and 2009 and helped the club win the 2006 FA Youth Cup. He made one substitute appearance for the first team, against Galatasaray in a Champions League match in December 2006.
While at Anfield Roque had loan spells with Oldham and Spanish sides Xerez and Cartagena before moving permanently to Betis in 2009, making his senior debut with the Spanish club in October 2010.
A Liverpool statement read: "Liverpool Football Club was today saddened to hear news that former player Miki Roque has lost his battle with cancer aged 23.
"Everyone at Liverpool Football Club would like to send their thoughts to Miki's family at this sad time."
Roque's death prompted an avalanche of tributes on Twitter, including from several Spain internationals competing at Euro 2012.
"A big hug for Miki Roque's family," central defender Gerard Pique wrote.
"I knew him when he played for Liverpool and I was at Manchester United. Rest in peace friend."