Towering No 1 seed Isner crashed out 6-4, 6-4 to fellow American Ryan Harrison in the second round and raised doubts about whether he will play in next week’s Australian Open with a bruised right knee.
French second seed Simon bowed out of the tournament without hitting a ball, succumbing to a recurring neck injury and giving an opportunity to lucky loser Ivo Klec to face Nieminen.
Finland’s Nieminen polished off the Slovakian world ranked 416th player 6-3, 6-1 in just 46 minutes to set up a quarter-final showdown with in-form Australian Bernard Tomic.
Big-serving Isner, who withdrew from last week’s mixed teams Hopman Cup in Perth with the injured knee, said he had a decision to make about playing in the year-opening Grand Slam in Melbourne.
“It’s better. Definitely better than I thought, but it’s not 100 per cent,” Isner said. “I don’t know. I’ve got a decision to make shortly. It needs rest. That’s what I’ve done. That’s the only thing I’ve done ever since I felt it last week, “ he added.
Simon also has injury concerns ahead of the Australian Open but is more confident than Isner of playing in Melbourne.
Nieminen will face a tough test against Tomic, who knocked out German fifth seed Florian Mayer, 7-6 (7/4), 6-2.
Italian third seed Andreas Seppi ended Australian wild card John Millman's run with a 6-2, 3-6, 6-3 win and will next play Spanish eighth seed Marcel Granollers, a straight sets winner over Italian Fabio Fognini.