Mills, 28, and Clark, 36, hold a 20-point lead going into the finale, after finishing second and third in Tuesday's races.
The duo missed out on gold at London 2012, taking silver as New Zealand edged them out in the medal race.
"It feel like we've been sailing forever to get this gold," said Clark.
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"It's completely surreal. We've sailed out of our skin in a marathon event."
The pair have dominated throughout the event, winning three races and finishing in the top eight in all 10.
However, a medal is now out of reach for male 470 pair Luke Patience and Chris Grube, who are sixth going in to the medal race.
Alain Sign and Dylan Fletcher stand a chance of claiming a medal in Thursday's 49er medal race, sitting fourth, but Charlotte Dobson and Sophie Ainsworth are seventh.
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Great Britain's Hannah Mills and Saskia Clark will win Olympic gold in the women's 470 sailing if they finish Wednesday's medal race.