The club said the operation will take place Thursday, and Vilanova likely will spend four days in a hospital followed by six weeks of chemotherapy and radiation.
The 44-year-old had a tumor removed from a saliva gland in November 2011. He took over as Barcelona’s coach from Pep Guardiola this season after passing medical checks.
Under Vilanova’s guidance, Barcelona is off to the best start in Spanish league history at 15-0-1. The club has 46 points, nine ahead of Atletico Madrid and 13 in front of Real Madrid.
“During this time, depending on his evolution, Vilanova may be able to combine treatment with his work regime,” Barcelona said Wednesday.
Assistant coach Jordi Roura is expected to take over the team for Saturday’s league game against Valladolid, Barcelona’s last match until Jan. 6.
“Very sorry to hear the news,” Barcelona midfielder Xavi Hernandez said on Twitter.
“All my strength and support to Tito Vilanova,” Spanish tennis star Rafael Nadal said on Twitter. “We are all with you so you may overcome this news step.”
This is the second case of a serious illness affecting Barcelona’s squad in recent years.
French defender Eric Abidal underwent surgery to remove a liver tumor from his liver in March 2011, returned to help Barcelona beat Manchester United in the Champions League final that May, then underwent a liver transplant this April. He has resumed training but has not played in a game this season.