Simmons is struggling with a knee injury he first picked up in match action and has since aggravated in training.
The 24-year-old Reds star strained his left knee in the recent 41-33 defeat to New Zealand in Dunedin, before slipping during shuttle runs in preparation for the Wallabies' opening tour match against England this weekend.
Simmons will now definitely miss that Twickenham tie as he looks at a minimum of two weeks on the sidelines.
He will also sit out the game against Italy in Rome and is considered a serious doubt for the trip to Ireland prior to the clash with Scotland at Murrayfield and the Millennium Stadium match up with Wales.
The news is a big blow for McKenzie and co given that Simmons was expected to partner James Horwill in the bolierhouse for much of next month.
Known for his athleticism, agility and application, Simmons is also the Wallabies' primary lineout caller. With neither Horwill nor likely replacement Sitaleki Timani particularly comfortable in that role, No8 Ben Mowen is expected to call the shots against England Italy at least.
"It's really disappointing to be without Simmo, who probably doesn't get enough recognition for the role he plays in this team, including as a lineout organiser and our top-tackling forward," said McKenzie.
"He plays a different game to James and Sitaleki so you'll see various subtle changes to the way the team functions without him."
Simmons suffered similar bad luck the last time the Wallabies were in Europe, although on that occasion his tour absence was more of his own making. A dangerous tackle just 15 minutes into the loss to France in Paris saw him suspended for eight weeks, meaning he didn't play in the last-gasp win over Wales.