The regatta, which is Philadelphia's largest sprint race, is also the largest youth regatta in the world.
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Kelly Drive will be closed in the city's Strawberry Mansion section for the event.
Detours have been in place since Thursday and will end Saturday at 8 p.m.
Until then, Kelly Drive will remain closed between the Strawberry Mansion Bridge and Fountain Green Drive in both directions.
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High school athletes travel to Philadelphia from all over the U.S. and Canada to compete against top-level rowing crews.
All the boats are lined up and ready to go, with nearly 1,000 boats expected to be used during the 2-day event.
The race starts at the Strawberry Mansion Bridge and then the rowers take the 1,500-meter course south toward the finish line, which is right before a big turn on the river.
The Stotesbury Cup Regatta is a sprint to the finish.
Stotesbury Cup Regatta: Student athletes participate in largest youth regatta in the world
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Every team prepares in their own way.
"Last night we watched 'Talladega Nights', so I'm going to 'shake and bake' today," said John Cavagnuolo of Ridgewood Crew.
That means they're ready to do their part to win, but the nerves are setting in.
"Our slogan is if you ain't first, you're last," Cavagnuolo said. "It's a little scary. There's a lot of teams here."
Last year, more than 4,700 high school athletes from roughly 180 schools packed the area.
"It's competitive. It's the biggest scholastic race of the season, but we just have to be prepared," said Chris Corigliano of Ridgewood Crew.
The young athletes will compete on the world stage on Friday and Saturday.
"It's a very good program. Kids can stay healthy. Kids can stay fit," said Dan Nguyen of Atlantic City.
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"I'm so excited, this is one of the funnest races because there's so many people there and so much to see," said Claire Van Mater of Gwynedd Mercy Academy Crew.
The first regatta was held in 1927. Officials say girls began rowing in the competition in the mid 70s and now young women make up more than half of the participating athletes.
"I mean, I think it's a great thing, especially for women in the industry now. I think it's a great thing," said Tessa Naldzin of Gwynedd Mercy Academy Crew.
"My sister's on the team, so I like to support them and we're all friends with all the girls. It's a pretty close team," said Nour Aboshady of Gwynedd Mercy Academy Crew.
It's also fulfilling for coaches and volunteers who keep coming back.
"This is my 45th Stotesbury Cup Regatta," said Mark Valenti, of Gwynedd Mercy Academy Crew.
The regatta is free to watch and is expected to draw a crowd of nearly 10,000 spectators.