Spurs narrowly pipped the Magpies to fourth place last campaign, but it has been all change at White Hart Lane this summer, with Villas-Boas replacing Harry Redknapp in the biggest managerial switch of the off-season.
Real Madrid-bound Luka Modric will not feature as he nears a move to the La Liga champions, while influential midfielder Scott Parker is out injured after undergoing Achilles surgery.
Villas-Boas is likely to implement a new 4-2-3-1 system, with Sandro and newly-capped England international Jake Livermore providing protection for a back four which is likely to see Vertonghen partnered by Younes Kaboul in central defence.
With the protracted permanent transfer of Emmanuel Adebayor still ongoing, Jermain Defoe will lead the Spurs attack, hoping to add to his England goal in midweek.
Newcastle were arguably the Premier League overachievers last season, but Alan Pardew will be optimistic that his side can match that finish this year.