The Edinburgh front-row forward fractured his arm in the first autumn Test, against Samoa, last month and is unlikely to recover in time.
It has been reported that Nel could face up to five months out.
The Edinburgh tighthead missed all of last season’s Six Nations due to a serious neck injury. But he recovered to play in Scotland’s Australaisan summer tour.
Scotland kick off their Six Nations campaign against Wales in Cardiff on 3 February.
Zander Ferguson and Simon Berghan will likely deputise for Nel.