Nowinski was one of the three finalists on WWE's (at the time trading as WWF) first series of Tough Enough, which Maven Huffman won. After failing to win the competition, Nowinski made appearances in independent promotions before being hired by WWF and entering its developmental territories. Nowinski competed as Chris Harvard, capitalizing on his status as an alumnus of Harvard University. Nowinski made his first major independent appearance in London, UK for the Frontier Wrestling Alliance promotion at its Lights Camera Action show on December 14, 2001. Nowinski competed in its main event teaming up with Alex Shane to defeat Drew McDonald and Flash Barker. Though this was the only show Nowinski did for the promotion, he regards it as the best promotion he has ever worked for outside of WWE.

On the June 10, 2002, episode of Raw, Nowinski debuted in WWE, helping william Regal beat Bradshaw in a European Championship match. Nowinski had a short-lived alliance with Regal, defeating Spike Dudley in his debut match the following week with Regal in his corner. Nowinski teamed with Regal on the June 24 episode of Raw, defeating Bradshaw and Dudley. Nowinski continued to feud with Bradshaw over the next few weeks, with their feud ending on the July 8 episode of Raw, where Nowinski teamed with Jackie Gayda in a losing effort against Bradshaw and Trish Stratus, while also trying to warming up Regal from his breakdown after he lost the European Championship to Jeff Hardy. Nowinski feuded with The Dudley Boyz (Bubba Ray Dudley and Spike Dudley) through the summer.

Nowinski defeated Tommy Dreamer on the September 9 episode of Raw. A week later, Dreamer attacked Nowinski in a classroom. Their feud ended on the October 14 episode of Raw, where Nowinski was once again successful in defeating Dreamer. Over the next few weeks, Nowinski claimed victories over Jeff Hardy and Booker T before starting a feud with his former Tough Enough trainer, Al Snow. After defeating Snow in two consecutive weeks, Maven began to help Snow against Nowinski. On the November 25 episode of Raw, Nowinski went against Maven in a match that ended in a no contest. Nowinski teamed with D'Lo Brown to defeat Snow and Maven on two occasions. Nowinski then continued his feud with Maven into 2003, where Test aligned himself with Maven for a few weeks, successfully defeating Nowinski and Brown on January 13, 2003 episode of Raw.

Nowinski played an integral role in the discovery of the fourth case of chronic traumatic encephalopathy (CTE) in a former NFL football player, former Pittsburgh Steelers offensive lineman Justin Strzelczyk, who was killed in an automobile crash in 2004 at age 36. Julian Bailes, the chairman of the department of neurosurgery at West Virginia University and the Steelers' team neurosurgeon during Strzelczyk's career, insisted to Nowinski over a phone conversation that he thought Strzelczyk's death, which was precipitated by strange behavior that some had labeled as "bipolar", was worth looking into due to its similarities to the Andre Waters case. Nowinski contacted Omalu, who discovered the brain was still available, and Nowinski called Mary Strzelczyk, Justin's mother, to ask for permission to Omalu to examine it for CTE. Omalu's positive diagnosis was confirmed by two other neuropathologists.

Later that year, Nowinski initiated an inquiry into the suicide of Andre Waters, a 44-year-old former NFL defensive back who shot himself on November 20, 2006. Waters had sustained several concussions over his career, and at Nowinski's behest, Waters' family agreed to send pieces of his brain to be tested. Bennet Omalu, a pathologist at the University of Pittsburgh announced that "the condition of Waters' brain tissue was what would be expected in an 85-year-old man, and there were characteristics of someone being in the early stages of Alzheimer's."

Since Nowinski's departure from WWE and the publication of his book Head Games, he has garnered a significant amount of media attention, making numerous appearances on networks such as ESPN and CNN to discuss sports-related head injuries. Nowinski continues to work as a consultant for Trinity Partners while serving as Co-Founder and President of the Concussion Legacy Foundation (CLF), formerly known as Sports Legacy Institute. The CLF was founded on June 14, 2007 in Boston, Massachusetts by Nowinski and Dr. Robert Cantu in reaction to new medical research indicating brain trauma in Sports had become a public health crisis. Dr. Cantu wrote the foreword in a 2012 update of Head Games to accompany the release of the documentary of the same name. Postmortem analysis of the brain tissue of former contact Sports athletes was revealing that repetitive brain injuries, both concussions and subconcussive blows, could lead to the neurodegenerative disease chronic traumatic encephalopathy (CTE). In addition, an absence of awareness and education on concussions, specifically proper diagnosis and management, was allowing the disease to proliferate. Finally, with brain trauma becoming the signature injury of the wars in Iraq and Afghanistan, this research/education model could also be applied to the military.

CLF, according to Nowinski, was founded to solve this concussion crisis in Sports and the military through medical research, treatment, and education & prevention. The initial vision of the CLF was to formalize neuropathological research and develop and treatment, via partnership with a top-tier university medical school. To that end, the CLF began such a partnership with Boston University School of Medicine (BUSM) in September 2008, collaborating in formation of its Center for the Study of Traumatic Encephalopathy (CTE Center). Subsequently, CLF has sought to develop ways to raise awareness of the issue and to directly educate coaches, athletes and parents. In 2009, it created a Coaches Concussion Clinic program. The CLF has been featured in articles in The New York Times, on news programs such as 60 Minutes and Frontline, and has appeared in various segments on CNN, ESPN, and other networks.

Nowinski is a co-director at the CTE Center of BUSM, where he works closely with Ann McKee, M.D., and other center experts, as a liaison making contact with athletes and families of deceased athletes, to further case studies that examine brain tissues impacted by CTE. Nowinski's work on concussion research has led him to act as a spokesperson for his fellow experts at the CTE Center (e.g., M.D./Ph.D. faculty members Robert Cantu, Ann McKee, Robert A. Stern, and Lee Goldstein); in this role he provides a voice for the field of concussion-related research and awareness. Nowinski appeared on Stan Lee's Superhumans as a non-medical expert on concussions. Hockey News listed Nowinski on its 2011 edition of the 100 Most Powerful people in ice hockey as one of the Top 40 under the age of 40. This recognition was attributed to his ability in getting hockey players to donate brain tissue after death.

In September 2015, the Sports Legacy Institute announced a rebrand and changed its name to the Concussion Legacy Foundation. The rebrand aimed to align the evolution of the organization’s programs with its name. The organization is still led by its co-founders, Nowinski and Dr. Robert Cantu. In the announcement, Nowinski states, “the original name reflected our singular focus on conducting chronic traumatic encephalopathy (CTE) research during our first year. The new name reflects the expansion of our programs – including concussion prevention and care, as well as accelerating treatment and a cure for post-concussion syndrome and CTE. We look forward to creating change to ensure that children can participate in Sports without worrying it will derail their life, and that parents and coaches are armed with the tools to help them provide a safer environment.”