The 27-year-old, who only moved to Mestalla on a permanent basis last year following a loan deal with an obligation to buy from Inter, made only seven appearances across the 2018-19 campaign, split between his parent club and a half-season loan spell with Barcelona.
The Colombia international’s limited opportunities saw him lose his place in his nation’s squad following his World Cup exploits in Russia, missing out on selection for this year’s Copa America.
Now, he will initially link up with the Serie A outfit on loan before joining for a reported €15m (£13.5m/$16.9m) fee, having agreed to a four-year deal.
Initially contracted to Udinese as a teenager, Murillo never made a senior appearance for the Italian team, instead spending the early stages of his career on loan with Cadiz and Las Palmas on loan.
He subsequently established himself as a regular for Granada in 2013 before making the move to Inter two years later, on the back of an international breakout performance for Colombia that saw him named in the Team of the Tournament at the 2015 Copa America.
He found his chances somewhat reduced in his second season at San Siro, and ultimately sealed a return on an initial loan to Spain to join Valencia, only for that to also falter over the past 12 months.
Murillo becomes the latest in a line of off-season recruits at Sampdoria as the club seek to build upon last season’s ninth-place finish.
Valencia meanwhile have effectively swapped goalkeepers with Murillo’s former club Barca bringing Jasper Cillessen on board with Neto heading in the opposite direction.