The news brings to an end his three-and-a-half year tenure, having joined the club in November 2013.
Karanka guided Middlesbrough to promotion last summer as they finished second in the Championship, a year after narrowly missing out by losing in the playoff final to Norwich.
However, his team have struggled in the Premier League this season, currently sitting 19th with just four wins from 27 games. Their last league win came against Swansea on December 17.
A statement on the club website read: “Middlesbrough Football Club can today confirm the departure of Head Coach Aitor Karanka. Following discussions, both parties have agreed that it is in the best interests of the club to make this change.
“The club would like to thank Aitor for all his hard work over the past three-and-a-half years and for the success, we’ve had during that time. We wish him all the best for the future.”