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.
The offensive is the Marines' first major operation since their recent deployment to Afghanistan.
It is also the first such operation under President Barack Obama's presidency.
The operation - codenamed Khanjar or Strike of the Sword - 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.
UK-led forces in Helmand launched their own operation to combat the Taliban insurgency last week, in what the Ministry of Defence described as one of the largest air operations in modern times.
Thousands of British forces under Nato command have been fighting the Taliban in Helmand since 2006, but there has been criticism that they have been overstretched and under-resourced.
Security aim
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, 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 in the village of Nawa.
Nawa and nearby Garmsir - south of the provincial capital Lashkar Gah - are key targets in the operation, as the area is considered a refuge for militants and no US or Nato troops have previously operated there in large numbers.
Capt Pelletier 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."
Troop numbers
As of June 2009, Nato's International Security Assistance Force had 61,130 personnel from 42 countries including the US, Canada, European countries, Australia, Jordan and New Zealand.
The US is the largest contributor, providing 28,850 soldiers.
It also has troops under Operation Enduring Freedom - mostly in the east of Afghanistan on the border with Pakistan - that are not under Isaf's command.
In December 2008 they numbered 17,100.
President Obama has pledged to send an additional 21,000 extra soldiers to Afghanistan, many of them redeployed from operations in Iraq, to help with training Afghan security forces and to tackle the insurgency.
Last week the commander of UK troops in Afghanistan, General Jim Dutton, denied that the battle against the Taliban was "a losing campaign".
Gen Dutton welcomed the planned increase in US troop numbers.
"I am convinced that the addition of those [US] troops is going to improve the security situation," he said.
