Before moving to the United States, McLaughlin recorded Extrapolation (with Tony Oxley and John Surman) in 1969. The album showcased McLaughlin as a guitarist of great technical virtuosity, power, speed, and inventiveness (such as the ability to play in odd meters).

He moved to the United States in 1969 to join Tony Williams's group Lifetime. He subsequently played with Miles Davis on his landmark albums In A Silent Way, Bitches Brew (which has a track named after him), Big Fun (where he is featured soloist on Go Ahead John) and A Tribute to Jack Johnson -- Davis paid tribute to him in the liner notes to Jack Johnson, calling McLaughlin's playing "far in." He returned to the Davis band for one recorded night of a week-long club date, which was released as part of the album Live/Evil. His reputation as a 'first-call' session player grew, resulting in recordings as a side-man with Miroslav Vitous, Larry Coryell, Wayne Shorter, Carla Bley and others.

The Mahavishnu Orchestra, John's 1970s electric band, featured violinist Jerry Goodman (later Jean-Luc Ponty), keyboardist Jan Hammer (later Gayle Moran / Stu Goldberg), bassist Rick Laird (later Ralphe Armstrong), and drummer Billy Cobham (later Narada Michael Walden). The band was respected the world over for their technical virtuosity and complex fusion of eclectic jazz and rock with hints of Eastern/Indian influence.

After the split of the Mahavishnu Orchestra, McLaughlin worked with the far more low-key, acoustic group Shakti. This group combined Indian music with elements of jazz and thus may be regarded as a pioneer of world music. John was one of the first westerners, if not the first, to attain any acclaim performing Indian music for Indian audiences.

Along with Carlos Santana, McLaughlin was a follower of the guru Sri Chinmoy, and in 1973 they collaborated on an album of devotional songs, Love Devotion Surrender, which included recordings of Coltrane compositions including A Love Supreme.

He has also worked with the respected jazz composer Carla Bley.

In the early 1980s he teamed up with flamenco guitarist Paco de Lucía and Larry Coryell (later replaced by Al Di Meola) as the Guitar Trio, the virtuoso talents of all three musicians equally on display. The Trio re-united in 1996 for a second recording session and a world tour.

In recent times he has toured with "Remember Shakti". In addition to original Shakti member Zakir Hussain, this group has also featured eminent Indian musicians U. Srinivas, V. Selvaganesh, Shivkumar Sharma, and Hariprasad Chaurasia.

His most recent recording project has been a ballet score, Thieves and Poets, released in 2003 along with arrangements for classical guitar ensemble of favourite jazz standards.