The draw for the tournament, which took place yesterday, pitted the Champions League winners against Nigel Adkins' Saints over the weekend of January 5 and 6, and both club and manager will be hoping that the club's fortunes have been dramatically altered by then.
Benitez has endured a tedious opening period since replacing Roberto Di Matteo last month, with a number of fans and pundits criticising the appointment after only two points were taken from his first three games in charge.
The Spaniard will have fond recollections of the FA Cup though, after he won it with Liverpool in 2006, but he will also have the added pressure of knowing that his predecessor was responsible for bringing home the FA Cup trophy last season, with Chelsea winning the cup in four of their last six attempts.
The knock-out tie will be the first time the Stamford Bridge outlet have met Southampton this season, with the side's December 15 game postponed due to Chelsea's involvement in the World Club Cup.
Whilst Benitez will be aiming to win over the Blues' support though, there will be no lack of atmosphere when West Ham host Manchester United in what is the pick of the all-Barclays Premier League ties in the FA Cup third round.
When the sides met in the league recently Sir Alex's side came out 1-0 winners, but the two have enjoyed many more memorable duels over the years.
In another exciting tie, Arsenal were drawn against Swansea just days after a deserved defeat to the Welsh side on London soil.
The loss, which saw Michu net twice, heaped further pressure onto Arsene Wenger, who will be desperate to earn some leeway with fans by producing a result.
Elsewhere, Newcastle were drawn against the Brighton side that knocked them out last year, while Man City will prepare to face Watford.