Brain holds a bachelor's degree in electrical engineering from Rensselaer Polytechnic Institute where he was a member of the Alpha Chi Rho fraternity. Brain went on to receive a master's degree in computer science from North Carolina State University (NCSU). Before founding HowStuffWorks, Marshall taught in the computer science department at NCSU and ran a software training and consulting company.

He currently resides in Cary, North Carolina with his wife and four children. He serves on the North Carolina advisory board of DonorsChoose.

He also maintains a website with, among others, essays on transhumanism and robots and an online science-fiction novel on that topic, Manna. Brain argues in his new Robot Nation series that automation will lead to structural unemployment, requiring a guaranteed basic income.

Marshall founded the website HowStuffWorks in 1998 and ran the site until 2007, when he sold it to Discovery Communications for $250 million. Since 2008, a television documentary with the same name has aired on the Discovery Channel.

His websites Why won't God Heal Amputees? and God is Imaginary were created to denounce monotheistic religions. He is an atheist who doesn't believe there are any gods.

He has also created and posted some widely-viewed online videos on this subject, such as " 10 questions that every intelligent Christian must answer". This is his most widely-viewed video on YouTube, having been viewed over 5 million times.