He was the founder, chairman, and CEO of Biovail Corporation, once Canada's largest publicly traded pharmaceutical company[3] with more than CA$1 billion in annual revenue.

Canadian Business magazine ranked Melnyk 79th on its 2017 list of Canada's 100 wealthiest people, with a net worth of CA$1.21 billion.

[8] After taking 100% control of Biovail in 1991, Melnyk oversaw the launch of its first major product, Tiazac, in 1996, and its best selling drug, Wellbutrin XL, was licensed for distribution in the United States in 2001.

[11] In 2019, Melnyk founded Neurolign Technologies Inc., a medical device company specializing in the diagnosis and treatment of neurological disorders.

[12] In 2015, the National Capital Commission (NCC) put out a request for submissions to redevelop the south and south-western sections of LeBreton Flats, a prime downtown Ottawa development site, 21 hectares (52 acres) in size.

[13] In April 2016, the NCC selected the RendezVous LeBreton proposal, which included 4,000 housing units, park space, a recreation facility with services for the disabled, a library (just off the defined redevelopment lands) and a new arena for the Ottawa Senators.

However, in November 2018, the NCC announced that "partnership issues" remained to be resolved with RendezVous, and that it might cancel the development and start over in January 2019.

[18] Melnyk's first foray into sports franchise ownership came in 2001 with the purchase of the St. Michael's Majors of the Ontario Hockey League (OHL).

At the time, the club played at the St. Michael's College School's Arena in Toronto, but Melnyk aimed to move the team to nearby Mississauga.

On May 10, 2012, Melnyk sold the St. Michael's Majors (now called the Mississauga Steelheads) to Elliott Kerr for an undisclosed price.

[20][21] In December 2020, the Ottawa Senators were listed by Forbes magazine as the NHL's twenty-sixth highest valued franchise at US$450 million.

[20] The team enjoyed some success on the ice under Melnyk's tenure, making the playoffs nine times, including a trip to the 2007 Stanley Cup Finals, losing in five games to the Anaheim Ducks, as well as the Eastern Conference Finals in the 2017 Stanley Cup playoffs, where they lost to the Pittsburgh Penguins in seven games.

[22] In 2017 Melnyk told reporters that he would be open to the idea of moving the franchise to a different city if the fanbase didn't make efforts to increase attendance at Senators' home games.

"[23] In early 2018, some fans in Ottawa had gradually become disillusioned with Melnyk's management style and perceived unwillingness to spend the money needed to build a championship-calibre team.

The video received considerable criticism from fans and media for its awkward presentation and for the owner's own characterization of his team as being "in the dumpster.

Despite earlier promising to make every effort to re-sign the star players, Melnyk later contradicted himself when he was quoted as saying that trading away Mark Stone had been "[planned] for some time" as part of the rebuild.