Managerless Tottenham will come up against former boss Juande Ramos after being drawn to face Ukrainian outfit Dnipro in the last 32 of the Europa League, while Swansea have been tasked with overcoming Serie A title hopefuls Napoli.
Ramos was in charge of Spurs for just under a year in 2007 before being sacked with the club bottom of the Premier League in the 2008-09 season having taken just two points from their opening eight matches.
The former White Hart Lane boss will therefore be intent on gaining a measure of revenge over Spurs, who announced the sacking of Andre Villas-Boas this morning despite the Portuguese overseeing a 100 per cent record in Europe this season.
Tottenham topped Group K with six wins from as many matches and will be regarded as one of the favourites to win the competition, with Villas-Boas paying the price for an indifferent start to the Premier League after a big-spending summer.
They will start as favourites against Dnipro, who finished second in Group E behind Fiorentina, while Greek side PAOK or last season's runners-up Benfica lie in wait after the draw was also made for the last-16 in Nyon.
Swansea face a much more daunting route after being paired with Napoli, managed by former Liverpool and Chelsea boss Rafael Benitez.
The Swans, unlike Spurs, were unseeded for Monday's draw and knew they would be given tough opposition.
Michael Laudrup may feel his side have received the harshest possible draw, with Napoli still seething from their elimination from the Champions League last week.
The Serie A side won four of six games to sit alongside Borussia Dortmund and Arsenal but settled for third in Group F due to an inferior head-to-head record against their rivals.
Should Swansea cause an upset, they will face either Portuguese champions Porto or Eintracht Frankfurt.
Napoli's domestic rivals Juventus were pitted against Turkish club Trabzonspor, Spanish outfit Valencia face a tricky tie against Dynamo Kiev of Ukraine, while Real Betis have been drawn to face Russians Rubin Kazan in the other stand-out matches of the draw.