A hamstring injury means the 31-year-old won't have the chance to add to his club tally of 143 goals in two spells when Spurs face Ukraine's Dnipro in the last 32 of the UEFA Europa League at White Hart Lane on Thursday.
The European tie had been pencilled in as Defoe's final match in a Spurs shirt ahead of his move to Toronto in North America's Major League Soccer.
But he will take the field at half-time to receive the applause of the White Hart Lane faithful one last time before he heads to Canada.
"Jermain Defoe is, possibly along with Jimmy Greaves, one of the best goalscorers this club has ever seen," Sherwood said Wednesday.
"Let's hope we can find another one like Jermain Defoe because he is all about goals and he always played with all his heart whenever he put on the shirt.
"Everyone appreciated his efforts and he certainly is a legend at this football club."
In Defoe's absence, Sours will look to strikers Emmanuel Adebayor and Roberto Soldado for goals as they look to overturn a 1-0 deficit from the first leg in Ukraine.
Soldado missed an open goal in that match and the Spaniard has scored just once in his past 11 games.
"Robbie knows his time has come and hopefully that will be tomorrow (Thursday)," added Sherwood.
"We know what he can do, he is a top player otherwise he would not be at the club. Now is the time for one to ricochet off his backside and go in and then he can go on a run like Adebayor has."
Sunday's 1-0 loss to Norwich left Spurs six points adrift of Liverpool in the race for a top four finish in the Premier League and a place in next season's UEFA Champions League.
Asked if their Europa League campaign was having a negative impact upon domestic results, Sherwood said: "I wouldn't use it as an excuse but the facts are our record isn't fantastic after games in Europe.
"But we want to progress in this competition, it means a lot to us. We are not blessed with trophies recently.
"It's a long competition. On quality you have to say the Champions League is hardest, but on endurance you have to say it's the Europa League. It is sapping.
"It was always going to be tough to get into the top four, there are more teams than ever fighting for it. But we know we still have an opportunity.
"If we beat Cardiff on Sunday and Liverpool lose at Southampton, then we still have to go to Anfield so you never know.
"But, with respect, if you can't beat Norwich away you don't deserve to be in the Champions League."