The four times world champion, 24 points behind Mercedes' Lewis Hamilton with nine of 21 races remaining, lapped the season's longest layout with a best time of one minute 44.358 seconds.
Red Bull's Max Verstappen, with tens of thousands of his Dutch fans expected to make the short trip across the border, was second and 0.151 slower on a largely uneventful morning with some spots of rain.
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Hamilton, last year's winner in the Ardennes forests from pole position, ended the session third and 0.318 adrift of his German rival.
Ferrari's Kimi Raikkonen, chasing his 100th podium this weekend and a four times winner at Spa, was fourth on the timesheets.
Vettel had expressed optimism on Thursday that Hamilton could be reeled in over the remaining races, some of which should favour Ferrari more than Mercedes.
"Points-wise we know that we are a little bit behind but I don’t think it’s anything that we can’t do," the German told reporters.
"I think it is has been looking for myself worse in past years and we still managed to turn it around by having the speed, so that will be the key."
Both Vettel and Hamilton will have upgraded engines, with Mercedes saying the Briton had a new turbocharger, engine and MGU-H and MGU-K motor generator units in his car.
Those parts were within his allocation for the season but his Finnish team mate Valtteri Bottas will incur grid penalties after being given a completely new power unit that exceeded his allowance.
Bottas was fifth fastest in the session, ahead of Red Bull's Daniel Ricciardo who suffered an engine injector problem.
Britain's Lando Norris made his grand prix weekend debut, taking Fernando Alonso's McLaren for the session, with the 18-year-old team reserve lapping faster than under-pressure Belgian race regular Stoffel Vandoorne.
Norris, who is also chasing the Formula Two title, lapped in 1:47.364 compared to Vandoorne's 1:47.452.
Vandoorne did only 13 laps compared to Norris's 26, however, with the local driver kept in the garage as the team investigated a possible leak on the car.
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Raikkonen leads second Belgian GP practice
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