The Anguilla-born 25-year-old joined the club in 2009 having previously played for his home island and the West Indies Under-19s side.
Hughes made his first-class debut against Middlesex in 2010 and scored 6,657 runs across all formats.
He hit a best of 270 not out against Yorkshire in 2013, four runs short of Derbyshire's first-class record.
"We would like to thank Chesney for his efforts for Derbyshire over the last seven years," Derbyshire's cricket advisory director Kevin Dean told the club website.
"He produced some memorable innings for the club, no more than his unbeaten 270 in 2013 at Headingley.
"Whilst it's disappointing that we were unable to agree terms on a new deal, we wish Chesney well for the future."
Batsman Chesney Hughes has left Derbyshire after failing to agree terms on a new contract at the County Ground.