A grand assembly of tribal chieftains, community elders and politicians began four days of debating the bilateral security agreement (BSA), which will shape Washington's future military presence in Afghanistan.
Hours before the meeting, US Secretary of State John Kerry said the two sides had finally agreed the text of the pact after months of difficult negotiations.
If the "loya jirga" assembly approves the BSA, it must then be passed by the Afghan parliament.
Karzai urged the 2,500 delegates to consider Afghanistan's "future prosperity" as they made their decision, saying the deal gave the country a chance to move on after more than 30 years of war.
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"The agreement gives us a chance to transition into stability," he said.
"This agreement provides us a transitional period to reach stability in the next ten years ahead of us."
Afghanistan goes to the polls on April 5 to elect a successor to Karzai, who must step down after serving two terms, and a credible election is seen as important to the country's future stability.
Karzai told delegates Afghanistan needed Washington's cooperation in ensuring a clean, fair ballot.
The deal will see 10,000 to 15,000 foreign troops remain in Afghanistan after NATO pulls out the bulk of its forces by the end of 2014, Karzai said.
And he gave a frank assessment of his often thorny relationship with Washington, his principal foreign backer.
"America does not trust me and I do not trust them. I have had struggles with them and they have spread propaganda against me," he said.
The Taliban have condemned the jirga as an American plot and threatened to target its delegates if they approve the deal.