Smith's troublesome left ankle flared up during Pakistan's three-wicket win at Kingsmead today and he was unable to field for the majority of the tourists' innings.
Team manager Dr Mohammed Moosajee said: "Graeme's chronic left ankle problem has surfaced again during this ODI series.
"We have been trying to manage him but unfortunately the impingement syndrome slowed him down today and he is quite symptomatic.
"As things stand, he is unlikely to play in the last ODI - but we will make a final decision tomorrow [Friday].
"He has had surgery on this ankle a while ago and I think the load and the volume of cricket for the year and particularly during this ODI series, has troubled him."
Pakistan's win levelled the series at 2-2, meaning Smith is set to sit out the deciding match on Sunday.