David Crocker, a member of the ARPANET research community, writing in the Washington Post said "The reports incorrectly credited [EMAIL's] author, a 14-year old in the late 1970s, as the 'inventor' of email, long after it had become an established Service on the ARPANET." Another computer Historian, Marc Weber, a curator at the Computer History Museum, said that by 1978, "nearly all the features we're familiar with today had appeared on one system or another over the previous dozen years", including emoticons, mailing lists, flame wars, and spam.

Writing for Gizmodo, Sam Biddle argued that email was developed a decade before EMAIL, beginning with Ray Tomlinson's sending the first text letter between two ARPANET-connected computers in 1971. Biddle quoted Tomlinson: "[We] had most of the headers needed to deliver the message (to:, cc:, etc.) as well as identifying the sender (from:) and when the message was sent (date:) and what the message was about." Biddle allowed for the possibility that Ayyadurai may have coined the term "EMAIL" and used the header terms without being aware of earlier work, but maintained that the historical record isn't definitive on either point. Biddle wrote that "laying claim to the name of a product that's the generic term for a universal Technology gives you acres of weasel room. But creating a type of airplane named AIRPLANE doesn't make you Wilbur Wright."

In 1978, as a 14-year-old high school student, he attended a summer program at the Courant Institute of Mathematical Sciences of New York University (NYU) to study computer programming; and then while a student at Livingston High School in New Jersey, Ayyadurai volunteered at the University of Medicine and Dentistry of New Jersey (UMDNJ) where his mother worked. There he created an email system to emulate the paper-based interoffice mail system then in use at the medical school. In 1982, he registered the copyright for his software, called "EMAIL", as well as for the program's user documentation.

Ayyadurai makes the controversial claim to be the "inventor of email". His claim is based on the software he wrote as a 14-year-old student at Livingston High School (New Jersey). In 1979—some sources say 1978—he wrote an implementation of an interoffice email system, which he called EMAIL.

Thomas Haigh, a Historian of information Technology at the University of Wisconsin, wrote that "Ayyadurai is, to the best of my knowledge, the only person to have claimed for him or herself the title 'inventor of email'." Haigh argued that while EMAIL was impressive for a teenager's work, it contained no features that were not present on previous electronic mail systems and had no obvious influence on later systems. "The most striking thing about Ayyadurai's claim to have invented electronic mail is how late it comes. Somehow it took him thirty years to alert the world to [his] greatest achievement". Haigh wrote that by 1980, "electronic mail had been in use at MIT for 15 years, Xerox had built a modern, mouse-driven graphical email system for office communication, Compuserve was selling email access to the public, and email had for many years been the most popular application on what was soon to become the Internet."

In 1994, Ayyadurai founded a company called Millennium Cybernetics, which produces email management software originally called Xiva and now called EchoMail. The software analyzes incoming email messages to organizations before either replying automatically or forwarding it to the most relevant department. By 2001, customers included Kmart, American Express, and Calvin Klein, as well as more than 30 U.S. senators to help handle constituent email. EchoMail competed with more established customer relationship management software that had an email component. On its website, EchoMail describes Ayyadurai as the "Inventor of Email".

In June 2005, Ayyadurai was charged with assault & battery after his girlfriend called police to report he had pushed and shoved her during an argument. According to a police report detailing the incident, Ayyadurai allegedly resisted arrest and attempted to stab the arresting officer with a pen. After he was taken into custody, an emergency 209A restraining order was issued against Ayyadurai banning him from having contact with her. In July 2017, this was revealed on The Howie Carr Show.

His undergraduate degree from MIT was in electrical engineering and computer science; he took a master's degree in visual studies from the MIT Media Laboratory on scientific visualization; concurrently, he completed another master's degree in mechanical engineering, also from MIT; and in 2007, he obtained a Ph.D. in biological engineering from MIT in systems biology, with his thesis focusing on modeling the whole cell by integrating molecular pathway Models. In 2007, he was awarded a Fulbright U.S. Student Program grant to study the integration of Siddha, a system of traditional Medicine developed in South India, with modern systems biology.

In 2009, Ayyadurai was hired by India's Council of Scientific and Industrial Research, India's largest science agency, by its Director general, Samir K. Brahmachari. CSIR was mandated to create a new company, CSIR Tech, that would establish businesses using the research conducted by country's many publicly owned laboratories. Ayyadurai reported that he had spent months trying to create a Business plan for CSIR Tech, but received no response from Brahmachari. Ayyadurai then distributed a draft plan, which was not authorized by CSIR, to the agency's Scientists that requested feedback and criticized management. His job offer was subsequently withdrawn five months after the position was offered."

A November 2011 Time Techland interview by Doug Aamoth entitled "The Man Who Invented Email" argued that EMAIL represented the birth of email "as we currently know it". In that interview, Ayyadurai recalled that Les Michelson, the former particle scientist at Brookhaven National Labs who assigned Ayyadurai the project, had the idea of creating an electronic mail system that uses the header conventions of a hardcopy memorandum. Ayyadurai recalled Michelson as saying: "Your job is to convert that into an electronic format. Nobody's done that before."

In February 2012, the Smithsonian National Museum of American History announced that Ayyadurai had donated "a trove of documents and code" related to EMAIL. The museum initially—inaccurately—cited the program as one of the first to include the now Common "subject and body fields, inboxes, outboxes, cc, bcc, attachments, and others. He based these elements directly off of the interoffice mail memos the doctors had been using for years, in hopes of convincing people to actually use the newfangled Technology."

Beginning in 2014, Ayyadurai was romantically connected with the Actress Fran Drescher. On September 7, 2014, Ayyadurai and Drescher participated in a ceremony at Drescher's beach house. Both tweeted that they had gotten married, and the event was widely reported as such. Ayyadurai later said it was not "a formal wedding or marriage", but a celebration of their "friendship in a spiritual ceremony with close friends and her family". The couple split up in September 2016.

In 2015, Ayyadurai published a paper that applied systems biology, which uses mathematical modeling, to predict the chemical composition of genetically modified (GM) soybeans and whether or not they were substantially equivalent to unmodified soybeans. The paper claimed that GM soybeans have lower levels of the antioxidant glutathione and higher levels of cancer-causing formaldehyde, making the modified soybean substantially different, contrary to previous safety assessments. The publication led to sensational headlines from opponents of GM foods. Shortly after publication, he embarked on a speaking tour of the US. At the National Press Club, he said that genetic modification had "fundamentally modified the metabolic system of the soy" disrupting the "beautiful way of detoxifying [formaldehyde]" present in non-GM soy.

In November 2016, the by-then-bankrupt Gawker Media settled the lawsuit with Ayyadurai for $750,000 as part of a broader settlement with Wrestler Hulk Hogan and Journalist Ashley Terrill, all of whom were represented by attorney Charles Harder. In a statement, Ayyadurai said that "history will reflect that this settlement is a victory for truth". Biddle denounced the settlement and said he fully stood by his reporting. Denton wrote that "we expected to prevail" in the Ayyadurai and Terrill lawsuits, "but all-out legal war with" Billionaire Peter Thiel, who financially backed Harder, was untenable in terms of cost, time and human toll.

In January 2017, Harder threatened the Diaspora Foundation with legal action unless it removed three posts by Roy Schestowitz that Harder alleged were "defamatory" towards Ayyadurai. (The Diaspora Foundation is part of the Free Software Support Network, which is in turn run by Eben Moglen and the Software Freedom Law Center.)

Ayyadurai also produced two controversial reports: the first questioning the working conditions of India's largest scientific agency; the second questioning the safety of genetically modified soybeans. Ayyadurai holds four degrees from MIT, including a Ph.D. in biological engineering, and is a Fulbright grant recipient. He is a candidate in the 2018 United States Senate election in Massachusetts.