Mattis told reporters that he thinks victory is still possible - defined as a political settlement with the Taliban.
Mattis planned to meet with Gen. John Nicholson, the top American commander in Afghanistan, as well as Afghan President Ashraf Ghani.
Conference participants will call for an urgent start of direct talks between the Kabul government and the Taliban, the press office of Uzbekistan´s foreign ministry said in a written reply to questions from Reuters. Ghani in February offered recognition of the Taliban as a legitimate political group as part of a proposed process he said could lead to talks. While the U.S. military says the strategy has hit the Taliban hard, they still control or contest much of the country.More news: China defends Duterte's commitment to 'fundamental rights' after United Nations criticism
Previous peace offers to the militants were refused. "And were they to reject it, then they would be responsible for the subsequent consequences".
It marks Mattis' third visit to the country, where about 11,000 US troops are stationed.
"I think we will succeed, and we hope and pray that our global friends and our regional friends will stay with us, and that people on the other side, the Taliban, will see that this is their best chance and we hope that they will take a chance that is offered earnestly and for the good of our people".More news: Federer backs Djokovic to improve after poor comeback
Most recently, nine people were killed in a suicide bombing on Friday, close to a ceremony on the death anniversary of Abdul Ali Mazari, a slain leader of the Islamic Unity Party of Afghanistan.
The attack is the latest in a string of violent incidents in the Afghan capital and the country as a whole.
The Taliban promptly claimed responsibility, with Taliban spokesman Qari Yusouf Ahmadi saying in a statement to the media that the group was behind the attack. Over the weekend, a Taliban attack killed seven army commandos and eight policemen in Bala Buluk district.More news: White House Fully Expects US-N. Korea Summit to Happen
CNN's Ehsan Popalzai contributed reporting to this story.