Fischbach first joined YouTube on March 6, 2012, creating a channel under the username "Markiplier", and uploaded his first video on April 4, 2012. Fischbach's first series was a playthrough of the video game Amnesia: The Dark Descent. After playing several other game series, including Penumbra and Dead Space, YouTube banned Fischbach's AdSense account. Though he appealed to YouTube as a last effort, the appeal was ultimately lost. Because of this, a new and current channel was created on May 26, 2012 and dubbed MarkiplierGAME.
Fischbach is primarily known for his playthroughs of indie and horror games, including the Five Nights at Freddy's series, Amnesia: The Dark Descent and its sequel, Garry's Mod, Happy Wheels, Surgeon Simulator 2013, Minecraft, and Slender: The Eight Pages, among others.
In 2014, he joined along side Arin Hanson, Brian Wecht and Dan Avidan to provide the vocals for one of the tracks on their album Player Select, titled Smash! which parodies Super Smash Bros.
Fischbach co-hosted the 2015 South by Southwest (SXSW) Gaming Awards with The Legend of Korra voice actor Janet Varney, and was featured prominently in YouTube's year-end special YouTube Rewind.
Fischbach signed with william Morris Endeavor in late 2016, having expressed interest in branching out from YouTube content.
In 2017, he embarked on his first improv tour, known as the "You're Welcome Tour", along with Ethan Nestor-Darling (CrankGamePlays), Wade Barnes (LordMinion777), Tyler Scheid (Apocalypto12) and Bob Muyskens (muyskerm), initially on a short four-date trip in mid 2017 before stretching to a full tour across North America and Europe in October 2017 through to 2018.
As of April 2018, his channel has over 9 billion total video views and 20 million subscribers, and is currently one of the Top 25 most-subscribed channel on YouTube. Fischbach specializes in Let's Play videos, commonly of survival horror video games.