Southee has been in tremendous form since snaring 7-64 in the first innings of the second test against India in Bangalore. He's taken 20 wickets in his last three tests, including the impressive match figures of 8-120 in New Zealand's 167-run win over Sri Lanka in Colombo last month.
His absence comes on top of those of Ross Taylor and Jesse Ryder for personal reasons and the injured Daniel Vettori, and will put more pressure on young left-armer Trent Boult and Doug Bracewell. It will also throw a curve ball into McCullum's plans to install Southee as vice-captain.
South Africa have some injury concerns of their own, with Vernon Philander in doubt for the first test starting on January 2 after a flare-up of his left hamstring. Philander, who took 21 wickets against New Zealand during last summer's home series, is expected to be out for up to two weeks.
Southee had been excused from the Twenty20 international component of the tour for the impending birth of his first child and was due to join the team for the two-test series. A replacement has not yet been called in but some consideration might be given to players like Mitchell McClenaghan, already in South Africa for the three Twenty20 matches, and it might be hoped Mark Gillespie will be fit in time.
The first Twenty20 international is played in Durban tomorrow morning (5am NZT) and the Black Caps head into the match on the back of an encouraging 24-run win over South Africa A on Wednesday morning (NZT).
McCullum said there was a "high level of excitement'' in the team as a largely young and unproven side take on a South African outfit also shorn of some of their top-line players and it was an "easy group to gel together'' as he prepares for his first series since being appointed captain on a permanent basis.
"The guys have prepared really well,'' McCullum said. "We had a good warm-up game the other day where we got to try out some combinations and see some guys in action. Obviously tomorrow is going to be a step up but we are really forward to it and see it as a huge opportunity for this team.
"They are enthusiastic and possess some really good skills and I think they fit into this team really well. It's quite nice to bring them all in at the same time so they can find their feet as one rather than trying to feel their way on their own. There are many unknowns from our point of view but we see that as exciting and an opportunity for those guys rather than being concerned about not knowing what you are going to get from them.
Hopefully that little bit of spontaneity that the new guys can bring to us can add a little bit of punch to our team as well.''
McCullum said they would make a couple of changes to the side that played against South Africa A, with Boult, Bracewell and Martin Guptill, who all sat out the tour opener, good bets to come in.