Daniel Foote, a career diplomat named to his post in July, said conditions in Haiti were so bad that US officials were confined to secure compounds. He said the "collapsed state" was unable to support the infusion of returning migrants.
"I will not be associated with the United States' inhumane, counterproductive decision to deport thousands of Haitian refugees and illegal immigrants," Foote said in a letter addressed to Secretary of State Antony Blinken that circulated publicly on Thursday.
The United States has returned 1,401 migrants from the camp to Haiti and taken another 3,206 people into custody, the Department of Homeland Security said on Wednesday.
Haiti, the poorest nation in the Western Hemisphere, has gone through profound instability in recent weeks, including a presidential assassination, gang violence and a major earthquake.
Filippo Grandi, the head of the UN refugee agency, warned that this week the US expulsions to Haiti might violate international law.
Foote submitted his resignation to Blinken on Wednesday, a State Department spokesperson said, adding that Washington was committed to the long-term well being of Haiti, as well as offering immediate help to returning migrants.
The resignation follows growing pressure on the administration of US President Joe Biden from the United Nations and his fellow Democrats over the treatment of Haitians in a sprawling impromptu migrant camp in Texas near the Mexican border.
Biden's handling of what Republicans portray as a crisis at the border - including record numbers of migrant detentions this year - has led to growing disillusionment from advocates who hoped for an end to deterrent measures brought in by his predecessor Donald Trump.
Foote's decision to leave was interpreted and welcomed by rights groups as a stern criticism of the administration's immigration strategy.
"A big bold move. And a big deal," said William O'Neill, a lawyer specialising in humanitarian, human rights and refugee law. "He will be missed."
As many as 14,000 people gathered in the camp en Del Rio, Texas last week. The population is now reduced to less than half by expulsion flights and detentions. Others have left the dusty riverbank on the Rio Grande for Mexico to avoid being sent home.
Wade McMullen, an attorney with the Robert F. Kennedy Human Rights organisation, said several hundred people, mostly pregnant women and parents with children, had been released in Del Rio, Texas, over the past several days.
Images of US border guards on horseback using long reins to whip at Black migrants at the weekend caused outrage within the White House and from rights groups.
On the Mexican side of the river early on Thursday, close to 20 police patrol cars lined the bank, overlooking the area where hundreds of Haitian migrants in recent days have crossed back and forth.
Migrants said they were awoken at 6 a.m. by the cars driving through the camp that has sprung up alongside the river, and fearful of being detained, some migrants chose to take their things and cross back to the US side again.