Frank admitted this week that his side are “desperate to win games” as they aim to avoid a relegation battle this season after falling dangerously close to the drop zone.
Romero is banned for four games after his red card at Old Trafford at the weekend as Frank relies on Radu Drăgușin to fill in for the Spurs captain who has had an issue with discipline since he joined the side.
He joins fellow defenders Ben Davies (ankle), Lucas Bergvall (ankle), Destiny Udogie (thigh), Kevin Danso (foot) and Pedro Porro (thigh) in those with defensive injuries in what will be a makeshift Tottenham backline.
Saturday's defeat to Manchester United marked the fifth straight Premier League match where Tottenham have conceded at least two goals in what has been a disasterous campaign so far.
Their chances of bouncing back against Newcastle are slim and their attack as well as control on the game will take a knock with injuries to James Maddison (knee), Dejan Kulusevski (knee), Rodrigo Bentancur (thigh), Mohammed Kudus (thigh) and Richarlison (thigh) ahead of the clash.
Tottenham are on a seven-match winless league run for the third time since the start of last season and host a Newcastle side at the Tottenham Hotspur Stadium, a side who drew 2-2 with the North London side last time out.