With midfielder Bernardo Silva giving one of his best performances for Portugal, the hosts did not even need a goal from captain Cristiano Ronaldo as they pulled level on 27 points with Switzerland and won the group on goal difference.
The unlucky Djourou put the ball through his own net four minutes before halftime and Andre Silva sealed the victory in the 57th minute with his ninth goal of the campaign.
The Swiss had led the group since beating Portugal 2-0 in Basel in their opening match in September last year and gone on to win all nine matches before Tuesday's encounter in Lisbon, while Portugal had won their subsequent eight.
Aside from a penalty shootout defeat by Chile at the Confederations Cup in June, the defeat by Switzerland was the only competitive game Portugal have lost since Fernando Santos took over as coach in September 2014.
Switzerland will now enter a playoff over two legs with another European group runner-up in November for a place in Russia. The draw for the playoffs will be held next Tuesday.
Ronaldo should have scored his 16th goal of the qualifying campaign when he was sent clear in the 78th minute but he over-elaborated as he tried to get around Yann Sommer and allowed the goalkeeper to claim the ball but the points were already safe.
"I always believed we could do it," said Santos. "I believed in the players and fortunately they gave me this present."
"When you have quality and organisation, you are always closer to winning. The whole 90 minutes weren't perfect, but fortunately we won and we are going to Russia."
DEFENSIVE MISFORTUNE
The Swiss were cool and comfortable for the first half hour, stringing together some neat moves in midfield, while Portugal were let down by poor crossing and struggled to get the ball to Ronaldo.
But after Silva had a rasping drive tipped away by Sommer, the hosts moved up a gear and went ahead with the help of some defensive misfortune for the visitors.
Eliseu fired in a low cross which Sommer parried, only for the ball to ricochet off Djourou into the net.
The hosts took control after the break and scored again with a superbly-worked goal. A quick exchange of passes freed Silva on the right and his low cross was turned in by Andre Silva at the second attempt to send the Estadio da Luz into raptures.
Swiss midfielder Granit Xhaka admitted that his side had not performed well enough. "Today, we were somewhere between bad and very bad," he said.
(Writing by Brian Homewood; Editing by Ken Ferris)
