The biggest show of people power was in Baltimore itself, where several thousand mostly young demonstrators paralyzed several city blocks in a major rally through downtown to City Hall.
Thousands more protested in New York, Boston and the capital Washington in solidarity.
The protests were overwhelmingly peaceful and good-natured, although New York police detained several demonstrators and emotions were running high.
What appears to be a growing movement for change was centered on Baltimore, where a rally that started at the main train station included black and white demonstrators, some of them linking arms and chanting: "No justice, no peace! No racists, no peace!"
Many in the march, which appeared to be gathering momentum, were high school or college students.
"We´re protesting the ongoing injustices that police have perpetrated on black men particularly. Police are trigger-happy and we need to stop that," Jonathan Brown, 19, a student at Johns Hopkins University, told AFP.
And he warned: "If you can´t get your way through non-violent means because the aggressor is violent, other action needs to be taken."
Some in the huge crowd held placards, one reading, "Killer cops deserve cell blocks." A few wore shirts with the words, "Amnesty International observer."
The 2,000 National Guard personnel who have flooded Baltimore this week kept a low profile, although authorities have said they are primed to swoop should the march spark unrest like that which flared following the funeral of Freddie Gray, 25, on Monday.
Gray´s death was the latest instance in the United States of a black man succumbing at the hands of police -- a situation that has stirred resentment among African Americans who believe they are targeted by police.
That anger also sparked coast-to-coast demonstrations in major US cities last year after a white policeman shot dead an unarmed black teenager in the St Louis suburb of Ferguson in August.
Baltimore authorities urged calm and warned that they would again enforce a citywide curfew beginning at 10:00 pm (0200 GMT Thursday) and lasting until 5:00 am.
Tuesday night´s curfew was largely respected, although police made 35 arrests during the night and warned that they were assessing the volatile situation minute-by-minute.
Maryland State Governor Larry Hogan said he had been "very encouraged" by the last 24 hours and said a semblance of normality was returning to Baltimore, a gritty city of 620,000 about an hour´s drive from Washington.