Workers want to be paid $15 an hour, double the rate for many employees at fast-food chains.
In New York City, about 300 protesters flooded into a McDonald’s near the Empire State Building.
The strike comes amid calls by President Barack Obama and some lawmakers to raise the US minimum wage.
Those members of Congress suggest bringing the current rate up to $9 an hour from $7.25, previously set in 2009.
Labor Secretary Thomas Perez, who is taking a lead role in the Obama administration’s higher minimum wage push, said: “For all too many people working minimum wage jobs, the rungs on the ladder of opportunity are feeling further and further apart.”
In addition to a walkout at fast-food chains in 50 cities, employees at retail firms in some cities were expected to join, say union leaders.
Workers say they cannot live on the minimum wage, which would net $15,000 a year for full-time work.
But many note they are rarely scheduled for full working weeks.
In a statement, McDonald’s and Burger King Worldwide said they do not make pay decisions at the majority of US restaurants that operate as independent franchises.
The firms have argued that raising entry-level wages would mean higher overall costs and higher prices.
A spokesman for the National Restaurant Association, a restaurant lobbying group, told the Associated Press news agency that low wages reflect the fact that most fast-food workers tend to be younger and have little work experience.
But Mary Kay Henry, of Service Employees International Union (SEIU), a labor group which is supporting the strike, says many fast-food workers are no longer only teenagers.
“The median wage [for service workers] of $9.08 an hour still falls far below the federal poverty line for a worker lucky enough to get 40 hours a week and never have to take a sick day,” Mary Kay Henry said.
The US fast-food industry has come under increasing scrutiny because part-time work, including retail and food positions, have made up most of the jobs added since the recession.
It is unclear if the strike will close any restaurants for the day, given that organizers announced the action with enough notice for managers to adjust work schedules.
Earlier this summer there was a one-day walkout by about 2,200 fast-food workers.
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