Hearts sealed their place in this stage of the competition after beating Hungarian club Paksi in new coach Paulo Sergio's first match in charge on Thursday.
However, the meeting with last season's Champions League quarter-finalists represents a huge test for the Edinburgh club.
"This is a very interesting draw for us, for sure," Sergio told Hearts' official website.
"No matter who we were drawn against it was going to be a very difficult tie but it is a match which I am sure will capture the imagination.
"There is not much travelling involved for the supporters and of course there will be the Scotland-England rivalry as well."
It will be the first-ever competitive meeting of the sides, although Spurs have twice played Scottish opposition, beating Rangers 8-4 on aggregate in the Cup-Winners Cup in 1962 and Aberdeen 5-2 in the UEFA Cup in 1973.
Elsewhere, 2010 Europa League finalists Fulham were handed a tricky-looking draw against Ukrainian club Dnipro Dnipropetrovsk, who are coached by former Sevilla, Spurs and Real Madrid boss Juande Ramos.
Birmingham City will meet Nacional of Portugal, while Stoke City's reward for beating Hajduk Split in their first European tie for 37 years is a meeting with Swiss club FC Thun.
Scottish champions Rangers, who were eliminated from the Champions League third qualifying round by Malmo, will meet another Champions League dropout in Maribor of Slovenia.
Celtic will meet FC Sion of Switzerland, and the surviving Irish representative Shamrock Rovers take on Partizan Belgrade.
Other standout ties include last season's Turkish league runners-up Trabzonspor against Athletic Bilbao of Spain, and Hannover, fourth in last season's Bundesliga, against two-time UEFA Cup winners Sevilla.
Source: AFP
Source: AFP