The Benfica forward headed in after just 55 seconds in Geneva to get the hosts off the mark in this campaign.
Seferovic dragged another effort wide in the second half but Switzerland needed goalkeeper Jonas Omlin on form.
He saved from Danilo Pereira, made a smart stop to deny Goncalo Guedes and thwarted Bernardo Silva’s from range.
Joao Cancelo curled over and Diogo Jota’s header was also saved by Omlin as Portugal – without Cristiano Ronaldo, who was rested – tried and failed to pull level.
They slip to second in the standings after Spain’s victory over the Czech Republic.