A lawyer for Machado's Vente Venezuela party said earlier in the day the staffers have always acted correctly.
The wife of Roberto Abdul, a member of the commission which planned the primary where Machado was elected the opposition's 2024 candidate, has confirmed his arrest, Alfredo Romero, head of non-governmental organization Foro Penal said on social media.
Foro Penal regularly defends political prisoners.
Abdul had previously been interviewed by authorities in connection with a criminal investigation into the primary, which the opposition has said was transparent and fair.
There are also arrest warrants for Henry Alviarez, Claudia Macero and Pedro Urruchurtu for crimes including treason, conspiracy and money laundering, Attorney General Tarek Saab said on state television in the afternoon.
The three staffers, along with Abdul, took part in "destabilizing and conspiratorial actions" against a recent referendum vote over a territorial dispute with Guyana, Saab said.
Voters in the referendum, backed by the government of President Nicolas Maduro, rejected an international court's jurisdiction over the long-running dispute and supported the creation of a new Venezuelan state in the Esequibo region, much to the chagrin of Guyana, which has questioned the vote's legitimacy.
The four people and allies abroad used "financing from money laundering by international organizations and foreign companies like Exxon Mobil" for their activities, Saab said, without providing more details.
Exxon operates its largest foreign oil project offshore of Guyana. CEO Darren Woods said earlier on Wednesday he expects the dispute to be resolved within a couple of years through international arbitration.
Exxon did not immediately respond to a request for comment on Saab's allegations.
Machado, who held a press conference nearly simultaneously to Saab, said the authorities "believe that with this they will create fear, imbalance, demoralization or demobilization, and it's just the opposite."
The three staffers were present at her event, she added, and have the full support of her party.
The party's lawyer, Perkins Rocha, said afterward in comments shared on social media there has been no official notification of the warrants.
"We are waiting for them to notify us, we want to know what it's about," Rocha said.
(Reporting by Vivian Sequera in Bogota and Sabrina Valle in Houston, additional reporting by Deisy Buitrago in Caracas and Kiana Wilburg in GeorgetownWriting by Julia Symmes Cobb; Editing by Lisa Shumaker and Shri Navaratnam)
By Vivian Sequera and Sabrina Valle