Van Aert fought hard in a finale that required the Jumbo-Visma rider to both overturn an eight-second deficit and fend off the fast-finishing Jordi Meeus (Bora-Hansgrohe) inside the final kilometre.
Having settled for second in each of the previous two stages, van Aert's victory in Stage 5 - ahead of Meeus and Ethan Hayter (Ineos Grenadiers) respectively - helped tighten his grip on the yellow jersey with three days remaining.
The 162.5-kilometre journey from Thizy-les-Bourgs to Chaintre was one for the fast men, though that didn't deter the field from several attacks, not least after the opening ascent of the Col des Escorbans.
Fabien Doubey (TotalEnergies), Jan Bakelants (Intermarché-Wanty-Gobert) and Sebastian Schönberger (B&B Hotels-KTM) moved clear of the peloton at this point, where they were later joined by Benjamin Thomas (Cofidis) and KOM leader Pierre Rolland (B&B Hotels-KTM).
With his points secured on the category 2 Cote de Dun, Rolland retreated back to the peloton, allowing the aforementioned quartet a near two-minute lead inside the final 50 kilometres.
Jumbo-Visma and BikeExchange-Jayco had moved to the front of the chase by that point, but the breakaway remained in control, cohesively navigating the category 4 ascents of the Col du Bois Clair and Cote de Vergisson with less than 30 kilometres to go.
Filippo Ganna did well to decrease the break's lead for Ineos shortly after, and it looked as though his teammate, Hayter, would benefit in a battle with van Aert.
But, again, the breakaway refused to budge, before Thomas opened his sprint with 400 metres of rolling roads remaining.
Despite the Cofidis rider's impressive display, it wasn't enough to deny van Aert in a tight affair that now sees the 27-year-old hold a 1'03" lead over Mattia Cattaneo (Quick-Step Alpha Vinyl) in the general classification.
"I have to thank all my teammates. I know everybody says it, but in the end if you watch today, all six others were there for me and that makes today’s victory more special,” van Aert said.
“Luckily, we had Christophe [Laporte] with a master pull in the end, and before that, I had asked the boys to do everything they could. And if even our GC guys of 60kg are pulling in the front, then you have to finish it off."
The Critérium du Dauphiné continues tonight on SBS and SBS On Demand, with coverage of Stage 6 commencing at 11pm (AEST).