Pieterse had won the previous two World Cup rounds and, despite forcing her rival into early errors, struggled to match the speed of Van Empel on the hard ground in the latter stages.
Shirin Van Anrooij (Baloise Trek Lions) crashed heavily on the opening lap allowing the leading duo a gap and was left chasing in third for the remainder of the race.
Van Empel, who had mixed training with racing during November, was in firm control after mastering the course taking victory by 34 seconds, while Pieterse had to settle for second.
Van Anrooij saw off the challenge of Denise Betsema (Pauwels Sauzen - Bingoal) and Inge Van der Heijden (777) in the battle for third to clinch her fifth World Cup podium of the season.
The World Cup leader said that she suffered from cold hands in the opening laps, which resulted in some small errors.
When asked if she was ‘simply the best?' Van Empel replied: “Not the first part of the race, maybe the second.
“At the first part of the race, my hands were really cold, so it was a bit not good with my handlebars. In the second part, I felt good again. I rode my own race, which was enough for the win.
“My focus wasn’t there (early on), but in the second part it was, so really nice.”
How it unfolded
Coming into the eighth World Cup round, Fem Van Empel (Pauwels Sauzen - Bingoal) had a healthy lead in the overall series after winning the opening four rounds.
However, the European Champion hasn’t had things her own way in recent weeks, with fellow Dutch woman Puck Pieterse (Alpecin - Deceuninck) winning the last two rounds.
The pair had looked evenly matched in the last round at Hulst before Van Empel crashed, allowing Pieterse to take a clear victory.
The Scheldecross at Antwerpen, which was cancelled last year after the COVID-19 pandemic hit, was back with a course including hard ground and a long sand section alongside the river Scheldt.
Former world champion and twice runner-up in Antwerp, Lucinda Brand (Baloise Trek Lions) wasn’t on the start-line due to suffering from a cold, and Ceylin del Carmen Alvarado (Alpecin - Deceuninck) was another non-starter.
Multi-discipline world champion Pauline Ferrand-Prévot (Ineos Grenadiers) was on the start-line for her first World Cup event of the season but pulled out midway through the race after falling back through the field.
Rivals Van Empel and Pieterse battled at the front away from the start while behind the two-time winner at Antwerp, Denise Betsema (Pauwels Sauzen - Bingoal), tangled on the first tight corner and lost time.
Pieterse pushed the early pace and was the only rider able to bunny-hop the barriers going clear, with Van Empel following.
Shirin Van Anrooij (Baloise Trek Lions) had finished on the podium in the last three rounds, including a win at Beekse Bergen and was forced to chase alone behind on the opening lap.
After almost reaching the leading pair, Van Anrooij slid on the sand and bent her handlebars, resulting in the under-23 rider falling back to the chasing group.
Despite her crash, Van Anrooij had responded well and was chasing just seven seconds behind the leaders after the opening lap.
The technical ability of Pieterse was starting to show with Van Empel making a small mistake in the sand and then on a steep bank, but she closed back to her rival quickly on both occasions.
On the second lap, Van Empel lost her balance in the sand as her rival regained a gap of five seconds while Van Anrooij was a further eight seconds back.
Once again, Van Empel used her power and running speed in the deeper sections of sand to pull her Dutch rival back again.
Inge Van der Heijden (777) was also in the medal battle, just nine seconds behind Van Anrooij at the conclusion of the second lap.
After being on the back foot in the first half of the race, World Cup leader Van Empel started to dictate the pace approaching the halfway point and distanced Pieterse as her rival made a small mistake in the sand.
Former footballer Van Empel then increased her margin on the small running section to six seconds entering the penultimate lap.
Put under pressure, it was now Pieterse who made a small mistake as the mountain bike rider was pushing her technical ability on the tricky sections to reduce the gap.
After her early crash, Betsema was finishing strongly, riding across to Van der Heijden with the pair chasing third place Van Anrooij.
At the front, Van Empel looked calm and in control on the fast course setting the fastest lap of the race and increasing her advantage to 16 seconds at the bell.
In the battle for third, Van Anrooij had responded and was 24 seconds ahead of Betsema and Van der Heijden entering the final lap.
Van Empel continued her relentless pace taking victory by 34 seconds from Pieterse, who was resigned to a second-place finish.
Meanwhile, Baloise Trek Lions rider Van Anrooij maintained her pace to finish third 18 seconds ahead of a fast-finishing Betsema.
