The explorer aims to cross 3,500 kilometres in seven to ten days aboard his hybrid hot air balloon the Generali Arctic Observer, travelling west over the North Pole to Alaska.
He will be tracked throughout by a team of technical and scientific experts on the ground, who will keep him informed of wind directions and weather conditions.
While in flight, up to 5,000 metres above sea-level, Etienne plans to make several scientific observations, including measuring carbon dioxide levels and studying the earth's magnetic fields.
Speaking over radio shortly after he set off, the explorer described the experience as "something extraordinary".
"It's a moment of great intensity. [...] Now everything's very calm. I'm rising steadily above Longyearbyen. It's absolutely magical."
The take-off was watched by French footballer Zinedine Zidane, who sponsored Etienne's expedition.
Etienne, a doctor from south-west France, became the first man to cross the Arctic on foot in 1986.
He first planned to make the crossing by balloon in 2008, but was forced to abandon the expedition when his balloon was severely damaged in violent storms two months before take-off.