US Gen David Petraeus is due to meet Pakistan's army chief on his first visit to the country since becoming head of US Central command, BBC reported.
The trip comes amid tensions between Islamabad and Washington over US missile strikes on suspected Islamist militants in northwest Pakistan.
Last Friday Gen Petraeus took control of US military operations throughout the Middle East and much of Asia.
His responsibilities include Iraq and Afghanistan as well as Pakistan.
The general is being accompanied by US Assistant Secretary of State Richard Boucher.
As well as meetings with Pakistani army chief Gen Ashfaq Kayani, the visit will include meetings with other senior political leaders.
The American envoys face the delicate task of explaining US actions without upsetting its ally, says the BBC's South Asia analyst Anbarasan Ethirajan.
The fact the visit is taking place just days after Gen Petraeus took up his new post shows how important the US considers Pakistan's role to be in its war on terror, our correspondent says.
US commanders in Afghanistan strongly believe the answer to reducing violence in the country lies across the border in Pakistan's north-west.
The restive tribal area is considered a haven for al-Qaeda and Taleban-linked fighters.
But despite recent US missile strikes and the deployment of extra Pakistani troops to the region, militant attacks have continued.
More than 20 people were killed in two suspected US missile attacks in northwest Pakistan on Friday. But just two days later, eight Pakistani soldiers were killed in a suicide bomb attack on a security base near the border with Afghanistan.
Gen Petraeus has already commissioned a major review of US strategy in the region, which is expected to emphasise the need for a wider regional solution and more outreach to the Taleban.
But Mr Boucher said last week it was unlikely there would be talks between Gen Petraeus and the Taleban.
"The issue is that both Afghanistan and Pakistan have policies on reconciliation and we have been, and continue to be, willing to support those policies," he told the BBC.
Iraq and Afghanistan are likely to dominate Gen Petraeus' agenda, says the BBC's defence correspondent Rob Watson.
Previously Gen Petraeus was commander of the US military in Iraq. He was widely credited with improving security there through the "surge" plan, which saw nearly 30,000 US troops deployed to trouble-spots.