Byrne has served as a Teaching Fellow at Stanford University; Chairman, President and CEO of Centricut, LLC; and Chairman, President and CEO at Fechheimer Brothers, Inc., a Berkshire Hathaway company.

In 2001, Byrne began Worldstock Fair Trade, an Overstock.com division selling handcrafted products from artisans in developing nations. Worldstock profits have been donated to fund philanthropic projects, including building 26 self-sustaining schools across Asia and Africa educating thousands of students. Byrne also created the Main Street Revolution marketplace for small American entrepreneurs, a pet adoption service that has connected people with 75,000 pets in less than two years, and Farmers Market which now makes fresh, locally grown produce available to 45% of the U.S. population.

In 2010, Forbes named Overstock.com the No. 9 Best Company to Work for in the Country, and Byrne the CEO with the highest employee approval rating (92%). In 2011, Ernst & Young gave Byrne its National Entrepreneur of the Year Award, and in 2014, Overstock.com was named one of the Most Trustworthy Companies in America by Forbes/MSCI ESG Research.

A “classical liberal,” Byrne believes that our nation’s success depends on educational choice and capital markets. Since Milton Friedman’s passing in 2006, Byrne has served as Chairman of EdChoice (formerly the Friedman Foundation for Educational Choice), an organization leading the national push for school choice. Toward the goal of clean capital markets, in 2004 Byrne began a vigorous citizen-journalist campaign focusing on regulatory capture, hedge fund mischief, settlement system failures, systemic risk, and the possibility of economic warfare against the U.S. by organized crime and foreign governments. His stance became a point of high controversy until the crash of 2008, occasioned by many of the things of which Byrne had warned. Byrne's website DeepCapture.com subsequently received much recognition, such as Weblogs Award "Best Business Blog" (2008), Business Pundit's "Best Business Investigative Journalism" (2009), and Xmark's "Top Site on Corruption in the USA" (2010).

In 2012, when no firm of $1 million in revenue yet accepted cryptocurrencies as a payment method, Byrne’s pro-freedom views led him to have Overstock.com, then with $1.4 billion in revenue, become the first major online retailer to accept Bitcoin. Having gained familiarity with blockchain technology at the heart of digital currencies such as Bitcoin, Byrne founded Medici Ventures, a subsidiary of Overstock, created to build solutions leveraging and servicing blockchain technologies. Medici project companies include: t0, focused on the development of financial technology (fintech) based on cryptographically-secured, decentralized ledgers. Since its inception, t0 has pioneered the effort to bring greater efficiency and transparency to capital markets through the integration of blockchain technology.

Byrne has a black belt in Tae kwon do, and once pursued a career in professional boxing. He is a cancer survivor, and has ridden a bicycle across the country to raise awareness and money for cancer research at the Dana Farber Cancer Institute.