The US military says about 4,000 marines as well as 650 Afghan troops are involved, supported by Nato planes.
Brigadier General Larry Nicholson said the operation was different from previous ones because of the "massive size of the force" and its speed.
Officers on the ground said it was the largest marine offensive since Vietnam.
It is the first such operation under President Barack Obama's presidency.
The operation began when units moved into the Helmand river valley in the early hours of Thursday.
Helicopters and heavy transport vehicles carried out the advance, with Nato planes providing air cover.
Southern Afghanistan is considered a Taliban stronghold.
"Where we go we will stay, and where we stay, we will hold, build and work toward transition of all security responsibilities to Afghan forces," said Brig Gen Nicholson in a statement.
At a briefing at the US military's Camp Leatherneck last week, he told personnel and embedded reporters: "One of the most critical things is to tell people why we're there, and we are going to have a limited opportunity to gain their trust."
The operation would have an initial highly aggressive stage lasting 36 hours, AFP news agency reported.
It aims to improve security ahead of presidential elections on 20 August 20, allowing voter registration where before there was none, Gen Nicholson said.
A US military spokesman, Captain William Pelletier, told the BBC there had been "no enemy contact" in the first hours of the operation, but one marine was slightly injured when an improvised explosive device detonated.
He said the US military was prepared for casualties, but stressed that "it is absolutely essential that no civilians be harmed".
Helmand Governor Gulab Mangal predicted the operation would be "very effective".
"The security forces will build bases to provide security for the local people so that they can carry out every activity with this favourable background, and take their lives forward in peace."
Obama strategy focus of Afghan talks
Delegates from 70 nations are gathering in The Hague to discuss reconstruction in Afghanistan, against the new backdrop of the major Obama strategy for the country unveiled last Friday.
President Barack Obama wants a modest increase in US troops, many more civilian advisers, and is hoping to engage wider regional support to improve security in Afghanistan.
The Hague meeting could see the first moves towards high-level contact between the US and Iran since the Islamic revolution of 1979 brought the Ayatollah Khomeini to power.
If it goes well, there is even speculation that the US will ask Iran if non-military equipment for Nato forces could be allowed to cross Iran.
'Investment for the world'
Afghan President Hamid Karzai will head a large team from Kabul, and his ambassador in the US, Said Jawad, made a passionate appeal that the world should not forget Afghanistan as it has done before.
At a pre-conference meeting, organised by The Hague Centre for Strategic Studies, he said: "Being in Afghanistan is dangerous, but not being in Afghanistan is a lot more dangerous, and we learnt this on 9/11.
"Being in Afghanistan is an investment for your children, for the future of Afghanistan and the world."
The political system that is emerging in Afghanistan may not have the most rigorous democratic standards, but the Bush years of believing that countries could be fixed by imposing a voting system from outside are over.
Said Jawad said there were other tests of democracy.
"If democracy means not fearing the secret police, having the opportunity to send your daughter to school, or the opportunity to give birth as a woman without fearing death - this is the right of every human being," he said.
"This is what every Afghan deserves and demands."
Although this conference will not make specific demands for cash, the need to raise more money is at the heart of the negotiations.
And a wider regional strategy demands that the money be raised more widely.
Nato Secretary-General Jaap de Hoop Scheffer said it would be "impossible" for Nato countries to find that money.
In an interview with the Financial Times before the conference, he said that other nations such as Japan, the Gulf States and Saudi Arabia should shoulder more of the burden.
"It is difficult to see how Nato allies, given the enormous amount they are spending keeping forces there, can bring in $2bn a year," he said.