Huffman, star of Desperate Housewives, and Full House actress Loughlin, are accused of taking part in an apparent scheme involving parents who paid bribes to get their children into elite universities, including Stanford and Yale.
Both were charged with conspiracy to commit mail fraud and wire fraud in indictments unsealed at a federal court in Boston.
Some 33 parents in total have been charged, as well as 13 other people.
“These parents are a catalogue of wealth and privilege,” said US Attorney Andrew Lelling, describing the scheme as the biggest college admissions scam ever prosecuted by the US Justice Department.
Federal prosecutors have charged William “Rick” Singer, 58, with running the racketeering scam through his Edge College & Career Network, which served several clients, including chief executives and Hollywood actresses.
Prosecutors said his operation arranged for fake testers to take admissions exams in place of clients’ children, and in some cases arranged for applicants to be listed as recruited athletes even if they had no athletic ability.
Part of the scheme also allegedly involved advising parents to pretend to test administrators that their child had learning disabilities, which allowed them extended time to take an exam.
The parents were then allegedly advised to choose one of two test centres that Singer’s company apparently said they have control over.
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Administrators there took bribes to allow Singer’s clients to cheat, often by arranging to have wrong answers corrected, or by having another person take the exam, according to the documents.
Parents paid tens of thousands of dollars for Singer’s services, prosecutors said.
Court documents claim Oscar nominee Huffman, who is married to actor William H Macy, paid $15,000 (£11,400) which she disguised as a charitable donation.
Huffman appeared in court where a judge said she could be released on a $250,000 (£191,000) bond. She is reported to have looked over to her husband several times during the proceedings.
Her attorney said: “She’s simply not the kind of person who is going to become an international fugitive.”
Huffman will appear in court on 29 March.
Singer pleaded guilty to charges including racketeering, money laundering and obstruction of justice, according to court papers. He could not be reached for immediate comment.
Stanford University sailing coach John Vandemoer also pleaded guilty.
In many cases, the students were not aware that their parents had arranged for the cheating, prosecutors said.
There is no suggestion that any of the universities were involved in any wrongdoing.
Loughlin’s spokesman did not offer a comment.
Huffman was not immediately available for comment.