The club's statement did not mention a transfer fee or how long the contract at Leeds would be, although reports in the Spanish media said the English club would pay Valencia around €30 million plus €10m in variables.
"Valencia have reached an agreement in principle with Leeds United for the transfer of Rodrigo, subject to the player passing a medical and all documentation and formalities being completed," said the La Liga side.
Known by his first name Rodrigo, he scored 59 goals in 220 games for Valencia. He is the latest high-profile player to leave after captain Dani Parejo and Francis Coquelin left for rivals Villarreal this month, sparking fresh protests against owner Peter Lim..
Rodrigo, 29, who spent time in the youth academies of Flamengo and Real Madrid before becoming a star at Benfica and then Valencia, is already well versed in English football, having appeared 17 times in the Premier League with Bolton while on loan from Benfica in the 2010-11 season.
"England was good to me. You go to England, you know the physical demands -- you've got no choice but to adapt and that makes you grow," he told the Guardian in 2018.
"Working there daily helped. I was involved, it was my first senior season and I learned a lot."
A wide player who attacks down the right wing, Rodrigo can link the forward line and is particularly effective on the counterattack.
His qualities have made him the favoured forward of Spain coach Luis Enrique and predecessor Robert Moreno. He has repaid their faith by scoring six goals in his last nine starts for his country.
He scored only seven goals in all competitions last season amid injuries and turmoil at Valencia, who sacked popular manager Marcelino in September and eventually finished ninth.
The 2017-18 season was his best in front of goal, scoring 16 in La Liga.
He also hit decisive goals against Ajax Amsterdam and Chelsea last year as Valencia reached the knockout stages of the Champions League and netted in the 2-1 win over Barcelona in the 2019 Copa del Rey final.