MacLean suffered an injury during his side's defeat at St Mirren Park on October 19 but looked on course for a comeback against Hearts last Saturday.
However, he suffered discomfort in the knee when he resumed full training on Friday and Saints announced that a scan "revealed the need for an operation which will result in an absence of at least three months".
The former Aberdeen striker will undergo surgery on Friday.
Meanwhile, Saints centre-back Steven Anderson has been told his dislocated thumb is not healing any quicker than expected, meaning he will be out for another seven weeks as predicted.
Manager Tommy Wright told the club's official website: "It's disappointing for everyone, not least the players, but we have to live with it and it is paramount that that we get it right medically.
"That's football and we'll just have to get on with it - their ongoing absence will continue to give opportunities to others to show what they can do."
Saints have won three consecutive games and kept three clean sheets with forwards Stevie May and Nigel Hasselbaink both among the goals and full-backs Dave Mackay and Tam Scobbie impressing in central defence.