His first commercial game was made at age 17: an independently developed point-and-click adventure game called The Palace of Deceit: Dragon's Plight. Bleszinski created the game while he was a student at Bonita High School in La Verne, California, and released it in 1991 via his own company, Game Syndicate Productions. He also sent a copy of the game to Tim Sweeney, the founder of Epic Games (then known as Epic MegaGames). Sweeney was impressed with the game and hired Bleszinski to work at Epic.
His next game was Dare to Dream, a point-and-click adventure, released in 1993. One of Epic's first multi-person projects brought Bleszinski's talents to bear on 1994's Jazz Jackrabbit and then 1998's Jazz Jackrabbit 2. He would help develop many of the spin-off games such as Jazz Jackrabbit: Holiday Hare. It was with his involvement in designing the first-person shooter Unreal, though, that Bleszinski began the work for which he is best known today. Unreal grew out of an idea by fellow Epic designer James Schmalz. Bleszinski felt that it was crucial to Epic that Unreal be a success. From the concept in late 1994 to release in May 1998, Epic threw all of its talent and money at Unreal, and it paid off: the result was a successful first-person shooter. In addition to his work on the Unreal series, Bleszinski served as lead designer on the Xbox 360 shooter Gears of War. The game's sequel, Gears of War 2 was released in November 2008 for the Xbox 360. On April 12, 2010, Bleszinski appeared on NBC's Late Night with Jimmy Fallon to show the debut trailer for Gears of War 3, called "Ashes to Ashes". Bleszinki's last game for the company was Gears of War 3.
Cliff announced his departure from Epic Games on October 3, 2012. He has worked in Epic Games for 20 years and decided to chart the next stage of his career, giving the reason that he had been making games since he was a teenager and that it was time for a break.
On July 29, 2013, Bleszinski published a post on his blog, pleading for Phil Fish to continue as a video game developer. He ended his post with the remark, "Come back, Phil. We miss you already. Maybe I’ll be right behind you, returning with Adamantium skin."
One of his brothers is Tyler Bleszinski, a sports blogger who founded Athletics Nation and Vox Media. He is married to Lauren Bleszinski (née Berggren), who is a blogger. The nickname "CliffyB" was given to him derogatorily by "some jock kid" when he was a shy teenager; he then took it and developed a tougher persona around it. In 2008, he expressed a desire to retire the CliffyB moniker, saying it's "time to grow up a bit". Bleszinski is an atheist.