The singer said it was "one of the most ignorant statements that anybody who came from the hood could ever say about their ancestors".
He also said Kanye's comments "broke my heart" and were "harmful".
Kanye earlier told TMZ: "When you hear about slavery for 400 years... for 400 years? That sounds like a choice."
He added: "You was there for 400 years and it's all of y'all? It's like we're mentally imprisoned."
He later tweeted to clarify that "of course I know that slaves did not get shackled and put on a boat by free will".
He added: "My point is for us to have stayed in that position even though the numbers were on our side means that we were mentally enslaved."
And then he claimed he was "being attacked for presenting new ideas".
That led to a wave of criticism from fans, fellow artists and others on social media - including the viral hashtag #IfSlaveryWasAChoice.
Asked about the comments on ITV's Good Morning Britain, Will.i.am said: "That broke my heart, because I thought about my grandma, who was born in 1920, and her connection with her mom who raised her, who was born in the late 1800s.
"And my grandmother's grandma, who was a slave. And when you're a slave, you're owned. You don't choose if you're owned. When you're a slave you're deprived of education. That's not choice, that's by force.
"So I understand the need to have free thought, but if your thoughts aren't researched, that is just going to hurt those that are still in conditions where it's not choice."
The musician said it "makes me want to cry that we're even talking about this" when there are problems in the world today that need addressing.
Will.i.am also said the comments seemed out of character for the Kanye he knows. "That's not Kanye," he said.
"To me, that's a different person that's saying that, and I hope it's not to raise awareness so you could sell a record and some shoes, because that would be the worst thing to do, to stir up this very touchy race situation and you be the benefactor from it.
"So I encourage you, if you really believe this, give your shoes away for free, give your album away for free. And I don't like talking about going against my community, but that is harmful."
He concluded: "I will not throw my ancestors under the bus to profit."
Others criticising Kanye included film director Spike Lee, who accused him on Instagram of making "uneducated comments" and urged him to "WAKE UP".
Lee wrote: "'SLAVERY... A CHOICE'??? My Brother, OUR ancestors did not choose to be stolen from mother Africa. OUR ancestors did not choose to be ripped of our religion, language, culture.
"OUR ancestors did not choose to be murdered, lynched, castrated, raped, burnt at the stake, families sold apart. OUR ancestors built this country (on land stolen from the Native Americans) from the ground up under the institution of SLAVERY."
On Twitter, musician Talib Kweli, wrote: "I will always have love for @kanyewest but bro out here putting targets on our backs. Slavery was not a choice."