The original application by Auckland-based Westpac Mussels Distributors was for a 125ha farm but it was scaled back by the commissioners, who also ordered it be kept at least 200m from the island.
The decision comes as the council considers a separate proposal for an oyster and kingfish farm inside Whangaroa Harbour.
Commissioner Rob van Voorthuysen said even in its scaled-back form the mussel farm would have adverse effects on the outstanding natural character of nearby Cone Island, small boat anchorages and customary fishing. Dolphins frequenting the area would also be displaced.
However, the commissioners believed that was outweighed by "significant economic benefits" for an impoverished part of New Zealand.
The proposal also had the backing of the island's owners, the Ririwha Ahu Whenua Trust.
A report by economist Fraser Colegrave predicted the farm would provide jobs for 87 people in Northland and boost the region's GDP by $5.5 million.
Pete Sehmb, spokesman for the Whangaroa Sport Fishing Club, said Northlanders would lose a valuable fishing ground and a safe haven for boating.
"For the small boat owners, when it's a bit snotty out there Stephenson Island is a safe place you can take the family out for a spot of fishing. This is a big chunk of water that will be lost to the community," he said.
The club would consider appealing to the Environment Court but cost was likely to rule it out.
Totara North man David Keys, spokesman for a proposed Whangaroa Maritime Recreation Park, was also disappointed, saying there were compelling environmental, recreational and scenic arguments against the farm.
"Most importantly there were more than 260 submissions against it, which is unprecedented in the Whangaroa area." The group would almost certainly appeal, he said.
The 35-year regional council consents will allow the company to farm mussels and collect spat as well as occasionally raising oysters, paua and scallops. It will have to lodge a $132,000 bond to pay for a clean-up in case the operation folds.
The proposal attracted 278 submissions when it was publicly notified in 2011 - 14 in support, two neutral, and 261 against.
Opponents have 15 working days to appeal.