Hearts will face Tottenham Hotspur, Rangers take on Maribor, while Celtic will play Sion in the play-off round of the Europa Cup.
Tottenham, who were seeded in the draw, will travel to Tynecastle for the opening leg on 18 August of the all-British clash against Hearts.
Rangers, who were seeded, will face Slovenian outfit Maribor and are away in the first leg.
Celtic too were seeded and will host the Swiss in their first leg.
Thirty-five third qualifying round winners had joined the 15 losing clubs from the Champions League third qualifying round and a further 26 teams who were beginning their European campaigns in Friday's draw at Uefa's headquarters in Nyon.
The 76 clubs looking to progress to the group stages were split into seven groups.
Hearts, who knocked out Hungarian side Paks on Wednesday after their first match under new manager Paulo Sergio, could have faced Spartak Moscow of Russia, Hapoel Tel-Aviv of Israel, Athletic Club of Spain and PAOK of Greece.
Instead, they were drawn against Harry Redknapp's Tottenham, who finished fifth in England's top flight last season, and will travel to White Hart Lane for the second leg on 25 August.
The London club have twice faced Scottish opposition, beating Rangers 8-4 on aggregate in the Cup-winners' Cup in 1962 and easing aside Aberdeen 5-2 in the Uefa Cup 11 years later.
Sergio, the Portuguese former Sporting Lisbon manager who took charge of Hearts after the dismissal of Jim Jefferies this week, said: "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."
Spurs assistant maanger Kevin Bond said: "It will be a tough tie. This will be a proper game over two legs and in no way, shape or form will we underestimate the challenge."
Rangers, who were knocked out of Champions League qualifying this week by Malmo of Sweden, had a one in five chance of travelling to Eastern Europe.
And they avoided being drawn against Dnipro Dnipropetrovsk of Ukraine, CSKA Sofia of Bulgaria, Spartak Trnava of Slovakia and Nordsjælland of Denmark.
Opponents Maribor have twice faced Scottish opposition, losing to Rangers themselves in the 2001 European Cup but thrashing Hibernian 6-2 on aggregate in the 2010 Europa League.
Maribor are the current Slovenian champions and, like Rangers, have dropped down from the Champions League, having beaten Dudelange before losing to Maccabi Haifa.
They are three games into their domestic league and sit joint top of the table with a 100% record.
Rangers manager Ally McCoist said: "It's a good draw in terms of the place that we are going to.
"It's accessible and it's not the worst. They are a good team and I think they are still sitting at the top of their league. They will be a tough side."
Celtic could have faced Slask Wrocław, the Polish side who knocked Dundee United out of the second qualifying round on away goals, Nacional of Portugal, Litex Lovech of Bulgaria, Ried of Austria and Rabotnicki of Macedonia.
They were drawn with Swiss side Sion, who were hammered 11-1 on aggregate by Aberdeen in the European Cup-winners' Cup in 1982 but avenged that result four years later.
Sion finished fourth in the Swiss league last season and, like Celtic, won their domestic cup competition, beating Neuchatel Xamax 2-0 in the final.
Celtic manager Neil Lennon said: "They are a good team, they have made a good start to the season, winning two out of three and, as with all Swiss teams, they will be very fit, very athletic and technically very good.
"It is a tough draw. There is no doubt about that."