Born in Matamata, Gregory trained as a journalist in Auckland and worked as a newspaper reporter in Northland before returning to study art history and English at Auckland University.

With one foot in the literary world, the other in the visual art realm, Gregory has been a prolific and busy presence on the cultural scene for nearly three decades. As Lara Strongman says " Greg O'Brien is one of New Zealand's most distinguished 'cultural odd job men'. As a curator, poet, novelist, art writer, and visual artist he makes major contributions to our culture. His great achievement is to uncover, and to bring into the light, the overlooked and undersung"

His first major collection of poems and drawings, Location of the Least Person was published in 1987, followed by Dunes and Barns (1988) and Man with a Child's Violin (1990). In the early 1990s, two collections were published in Australia: Great Lake (1991), Malachi, (1993). The collection Days Beside Water, (1993) was co-published by Carcanet, in the UK, and Auckland University Press. Other collections (and a host of small press productions) ensued.

Increasingly, during the 1990s, Gregory found himself writing about the visual arts. Lands and Deeds; Profiles of Contemporary New Zealand Painters (1996) kicked off a busy few years of art-writing and curating exhibitions. While holding a part-time position at City Gallery Wellington, he curated major exhibitions by Ralph Hotere, Rosalie Gascoigne, Colin McCahon, Fiona Hall, Laurence Aberhart, John Pule, Elizabeth Thomson and others. Presently, he is curator of the Graham Percy exhibition, which is touring the country until 2014, and he is a co-ordinator-participant in the ongoing 'Kermadec' art project.

Welcome to the South Seas won the 2005 Non-Fiction Award at the NZ Post Book Awards for Children and Young Adults

Gregory's two books of art for young people, Welcome to the South Seas (AUP, 2004) and Back and Beyond (AUP, 2008) were widely acclaimed and picked up various awards. His other non-fiction books include After Bathing at Baxter's - Essays and Notebooks (VUP, 2002) and News of the Swimmer Reaches Shore (Carcanet/VUP, 2007). His picaresque novel with illustrations, Diesel Mystic (1989) has, by various accounts, gathered a cult following in recent years. For some years, Gregory taught a poetry paper at Victoria University of Wellington and, between 1999 and 2006, was a regular commentator on Kim Hill's radio programme.

Among Gregory's other work is a collection of interviews with twenty-one New Zealand writers, Moments of Invention (1988, with photographs by Robert Cross), a monograph on the painter Nigel Brown (1991), and A Nest of Singing Birds; 100 Years of the School Journal (2007). With his partner, poet Jenny Bornholdt, he edited a collection of New Zealand love poems, My Heart Goes Swimming (1996) and The Colour of Distance New Zealand Writers in France, French Writers in New Zealand (2005). With Louis St John, he edited the bestselling Big Weather: Poems of Wellington (revised edition, 2009). Recent publications include A Micronaut in the Wide World: The Imaginative Life and Times of Graham Percy (2011), a collection of poems Beauties of the Octagonal Pool (2012) and a monograph on the painter Pat Hanly (2012).

Gregory was awarded the Sargeson Fellowship (1988) and the writing fellow at Victoria University (1995). He was first winner of the Landfall Essay Competition Prize (1997); An Anthology of New Zealand Poetry in English which he edited with Jenny Bornholdt and Mark Williams, received the Montana Poetry Book of the Year award in 1997; Parihaka: The Art of Passive Resistance, (co-edited by Te Miringa Hohaia and Lara Strongman) was joint winner of the Montana Award for History and Biography at the 2001 Montana New Zealand Book Awards; Welcome to the South Seas won the Non-Fiction Award at the 2005 New Zealand Post Book Awards for Children and Young Adults and the Elsie Locke Award at the 2005 LIANZA Children's Book Awards.

As an artist, Gregory has held solo exhibitions and participated in group shows in Auckland, Wellington and elsewhere. He has illustrated the work of other New Zealand writers - among them C. K. Stead, Elizabeth Smither, Bill Manhire, Michael King and Jenny Bornholdt. His artworks can be found on book covers in New Zealand, Australia, England, Germany, Holland and Russia. In 2012 he illustrated Kate De Goldi's novella, The ACB with Honora Lee, as well as his own book, Beauties of the Octagonal Pool. With his handprinter-brother Brendan, he has produced numerous small press editions bringing together poetry and art, by his own hand and by others.

Residencia en la tierra, 2011, acrylic on canvas, 970 x 710mm

Since 2008, he has made over 30 etchings with master printmaker Michael Kempson at Cicada Press, University of NSW, Sydney. He has also worked collaboratively with John Pule and Euan Macleod on ongoing series of etchings and paintings. Gregory has exhibited regularly at Bowen Galleries, Wellington, since 1990. In 2009, he exhibited 'For Maxwell Fernie I & II' at Peter McLeavey Gallery Wellington. He also held two solo shows at Jane Sanders Art Agent, Auckland. In October 2012 his work featured in the public art initiative 'Slot' in Redfern, Sydney.

His art is included in the collections of the Hocken Library, Otago University, Dunedin; the Alexander Turnbull Library, Wellington; the Ministry of Foreign Affairs collection; the University of Auckland Art Collection and the Chartwell Collection.

As poet and visual artist, Gregory O'Brien has worked with Doris De Pont on a range of fashion garments (Winter 2006). Composers Helen Bowater, Gillian Whitehead and Ben Hoadley have set his poems to music. His poetry and art have also found their way onto ceramics, badges and even a mural in a school hall on Rapa Nui / Easter Island.

Gregory received an Arts Foundation Laureate Award in 2012. The Laureate Award is an investment in excellence across a range of art forms for an artist with prominence and outstanding potential for future growth. Their work is rich but their richest work still lies ahead of them. The Award recognises a moment in the artists' career that will allow them to have their next great success. In the same year, Gregory was the recipient of the Prime Minister's Award for Literary Achivement for Non-fiction.

At the end of 2013 Gregory was acknowledged in the New Year's Honour's list as a Member of the New Zealand Order of Merit and in May 2017 received an honorary doctorate at Victoria University of Wellington​. "Victoria University Chancellor Sir Neville Jordan says the honorary doctorate is an acknowledgement of Mr O’Brien’s ongoing contribution to, and celebration of, artistic life in New Zealand."