Bono told the audience he would continue his Third World Drop the Debt campaign and put further pressure on G8 summit leaders to do something on the issue.
To loud applause, he said the campaign showed that an African life was worth "as much as a European or American life".
During the song Bullet The Blue Sky, Bono mixed in lyrics which called on paramilitary groups, such as the IRA, UDA and UVF, to get rid of their guns.
The band's older material, such as Sunday, Bloody Sunday and Where the Streets Have No Name, were warmly received.
The concert ended on a sombre note with a tribute to Bono's father, Mr Bob Hewson, who died last week. His face was beamed onto the huge screens dotted around the arena. Earlier Bono dedicated the song, Kite, to his father, who, he said, gave him his love of music.
U2 came on stage at about 8.30 p.m. and immediately launched into Elevation, a track from their current album All That You Can't Leave Behind.
The set also included several political references. At one stage an image of actor Charlton Heston, head of the National Rifle Association (NRA) in the US, appeared on the big screens. It was followed by a photograph of a young black girl picking up a handgun from the ground.
U2 have previously criticised groups such as the NRA for defending gun ownership.
Gardai described the event at Slane as "good-natured", with little trouble. There were 12 arrests, mainly for public order offences, and 142 drug seizures, Supt Eamon Courtney, who led the massive security operation, said. There were no fatalities and gardai successfully sealed off the river Boyne, which adjoins the site.
A court was in session at Slane village during the day but no concert-goers appeared before it, Supt Courtney said. He said the drugs seized were mainly small amounts of cannabis and ecstasy.
He said nobody was charged but they might be at a later date.
About 200 forged tickets were confiscated, although he said many of the holders were unaware they were fakes. "There were no assaults and no drownings this year, so we would like to thank the public for their co-operation," he said.
He said the 800 gardai involved hoped next Saturday's concert would be equally uneventful.
Local property was protected, he said, with only one window broken on Friday night. "For a crowd of this size, the whole thing was very good-natured and peaceful," he said.
U2 last appeared at Slane 20 years ago as virtual unknowns, supporting Thin Lizzy.
They marked their return to the Co Meath venue with a rousing set which included a tribute to the late Thin Lizzy singer Phil Lynott.
Earlier bands, such as Relish and Coldplay, were received with polite applause and occasional audience participation, but it was not until the American group Red Hot Chili Peppers hit the stage at about 6 p.m. that the crowd warmed up.