Friday’s draw for group stages of the tournament due to be hosted in Qatar this winter placed England in Group B alongside the USA, Iran and one of the three sides vying for the final European play-off spot.
Scotland, if they make it past Ukraine and Wales to qualify, will take on the USA on the opening day of the finals at 1pm GMT on November 21, in what will be a first competitive international between the countries after seven previous friendly meetings.
Next up would be Iran, and a potential first meeting since the infamous 1-1 draw at the 1978 World Cup in Argentina. Kick-off for that match is scheduled for 7pm GMT on November 25, while Scotland’s third game would see them face England at 7pm GMT on November 29.
Southgate said: "The advantage of being in pot one based on our seeding is that most of the draws we've had ... you avoid the biggest teams.
"There's obviously then some tricky ties and this is one of those groups where you're looking and thinking 'some of these are potentially trickier than just the rankings'. That's always a danger.
"It's intriguing isn't it, because we've never played Iran. And then the States ... I've met (US coach) Gregg (Berhalter) a lot recently, so we've had some good chats and he's got them vastly improved.
"The third game is going to be a highly emotional game whoever it is. We all know where our thoughts are with Ukraine and we have to see whether they are even able to play or not.
"And of course if it's one of the British teams, we've been through that in tournaments recently. So they become unique games, really. Form is totally out of the window."
England and Scotland have never previously met at a World Cup but they do have recent tournament history having battled out a goalless draw in last summer's Euros at Wembley.
Playing on the tournament's opening day means there will be just eight days between the Premier League's final games on November 13 before its winter break and England's first match at the World Cup.
Southgate did not see it as a major hurdle, and added: "It would only have been one or two days different if we had started later. We've known that we have to be really well organised on that.
"It might mean you could have a few players ruled out of the first game for that reason. But I think they are talking about a slightly increased squad (up to 26) anyway. We'll have a team!"
Hosts Qatar will face Ecuador on November 21 but it will be Senegal and Holland who play the opening game earlier that day, according to a match schedule released by FIFA.
Other draw highlights include two former world champions, Spain and Germany, being paired together in Group E.
World champions France were placed alongside Denmark in Group D, while Group C also looks tough, with Argentina, Mexico and Poland pooled together alongside Saudi Arabia.