The nonlinear, 19-mile route winds north from Watts to Huntington Park, then south to Lynwood and extends east to the Los Angeles River.
Area roads will remain closed until 5 p.m.
The car-free event encourages residents to rediscover Los Angeles from a different perspective. The goal is to promote a cleaner environment and good health.
Previous CicLAvia routes have snaked through downtown, East Los Angeles, the Westside and along Wilshire Boulevard.
The event is modeled after the "open streets" festival in Bogota, Colombia, which began nearly 40 years ago.
At various stations and hubs along the routes, participants can see live musical and dance performances, line up at a food truck, get their face painted and even take a Zumba class.
CicLAvia's organizers are also trying to boost the event's economic impact, encouraging businesses to stay open even though streets are closed and coordinating special offers for CicLAvia riders and walkers. A 2013 UCLA study found that sales for businesses along CicLAvia routes increased by anywhere from 10 to 57%.
The car-free events, run by nonprofit CicLAvia, began in 2010 with a route that stretched from East Hollywood to Boyle Heights. The most recent event in March followed a four-mile route that stretched through Pacoima, Arleta, North Hills East and Panama City.
The festival's organizers picked Southeast Los Angeles for Sunday's event because it was a "dynamic, vibrant and often under-served" community, said CicLAvia Executive Director Romel Pascual.
The open-air street festivals now happen about four times a year and draw, Pascual said, about 50,000 to 100,000 people each time. Pascual wants to make it a monthly occurrence.
"When you get out of your car and get on a bike and walk through these different communities, you realize you share things in common," he said.