Spiller was initially expected to be out for a matter of weeks after it was first diagnosed he would not need an operation following a tackle from behind by Southend's Anthony Grant in the club's 1-0 defeat at Southend in mid-September.
But subsequent problems with his ankle mean he will now need to go under the knife and is unlikely to play again this year.
Manager Andy Hessenthaler told the club's official website: "Danny's had a bit of bad news and it looks like he is going to need surgery, which could put him out for the next three months.
"We thought it was only going to be three weeks but he's got some complications with his ankle so it looks more like 12. That is a real blow for him, Spills is devastated I have to say."
The news comes as Hessenthaler considers recalling Simon King from his loan spell at Plymouth with defenders Garry Richards, Danny Jackman, Matt Fish and Joe Martin facing late fitness tests ahead of Saturday's meeting with Port Vale, and Andy Frampton and Barry Fuller already ruled out.