McCready was born in Pensacola, Florida, USA, but his family moved to Seattle shortly after his birth. As a child, his parents played Hendrix and Santana, while his friends listened to KISS and Aerosmith; McCready would frequently play bongo drums. At the age of 11, McCready purchased his first guitar and began taking lessons—aiming to imitate Gene Simmons of KISS, by sticking his tongue out.

Shadow split up soon afterwards, and McCready lost interest in guitar for some time, before finally joining another band called Love Chile. A high school friend, Stone Gossard, heard the band, appreciated McCready's work, and asked if he wanted to join a band he was forming. The two worked together and recruited bassist Jeff Ament. Together with drummer Dave Krusen (who would later be replaced by Matt Chamberlain, then Dave Abbruzzese, then Jack Irons, and currently Matt Cameron) and Eddie Vedder, the group formed the band Pearl Jam (originally known as Mookie Blaylock).

It was during this time that McCready took a central role in the Temple of the Dog project, combining members of Soundgarden and Pearl Jam. Mikes first recording studio experience was recording the Temple of the Dog album, including an epic 4-minute-plus solo for "Reach Down." According to drummer Matt Cameron, Mike's headphone monitors flew off halfway through the recording of the solo, and he played the rest without being able to hear the backing track. Mike still considers this track to be his greatest achievement.

By the end of 1991, Pearl Jam became one of the most famous modern bands with the release of Ten. McCready frequently soloed, and added a blues touch to the music (influenced by Stevie Ray Vaughan). McCready's guitar style is usually an aggressive bluesy nature, and he never plays the same solo twice. His live renditions of songs have slightly different solos due to his fondness of improvization, and sometimes he treats the crowd to a full-on improv. He is extremely energetic live, and is commonly found dashing around the stage, playing to the crowd, throwing plectrums and soloing with the guitar behind his head.