Spurs sit two points above West Ham United, who are in the final relegation place, with a goal difference advantage of 13 goals and a game in hand. West Ham's 3-1 defeat to Newcastle United on Sunday means Tottenham are mathematically safe from a first relegation since 1977 if they take two points from their final two games — at Chelsea and then at home to Everton.
De Zerbi, who was appointed in March and has taken eight points from a possible 15 since arriving, spoke with characteristic directness ahead of the trip to a ground where Tottenham have won just once in 35 league visits.
"We have to find new motivation from this pressure. If everyone wants Tottenham relegated, it's a big motivation for me and I hope for my players as well. We have to accept that football is nice because of the rivalry. It's good to imagine ourselves celebrating the win in their stadium."
He expanded on the psychological dynamic he wants his players to embrace.
"It's a motivation, it's a challenge. If a challenge is tougher, it's better for us to find new motivation and to be focused on staying together from the beginning to the end of the game. The pride, if everyone wants Tottenham relegated, I think for one Tottenham player, one Tottenham fan, all the people who work inside Tottenham — it has to be the biggest motivation."
Despite the mathematics favouring a cautious approach, De Zerbi was emphatic that his side will prepare only to win.
"We can't start the game thinking to draw. We have to start the game, prepare the game and speak in the meeting to win. Everybody wants to stay up, everyone wants to achieve this goal and then we can speak about everything."
Guglielmo Vicario is available after injury, though De Zerbi hinted he may remain with Antonín Kinský in goal. James Maddison could feature after returning from the bench against Leeds United last week. Dominic Solanke will miss out.