Zerzan was born in Salem, Oregon to immigrants of Bohemian heritage. He received his bachelor's degree from Stanford University and later received a master's degree in History from San Francisco State University. He completed his coursework towards a Ph.D. at the University of Southern California but dropped out before completing his dissertation.

Zerzan's theories draw on Theodor Adorno's concept of negative dialectics to construct a theory of civilization as the cumulative construction of alienation. According to Zerzan, original human societies in paleolithic times, and similar societies today such as the !Kung, Bushmen and Mbuti, live a non-alienated and non-oppressive form of life based on primitive abundance and closeness to nature. Constructing such societies as a kind of political ideal, or at least an instructive comparison against which to denounce contemporary (especially industrial) societies, Zerzan uses anthropological studies from such societies as the basis for a wide-ranging critique of aspects of modern life. He portrays contemporary society as a world of misery built on the psychological production of a sense of scarcity and lack. The history of civilisation is the history of renunciation; what stands against this is not progress but rather the Utopia which arises from its negation.

Zerzan is an anarchist, and is broadly associated with the philosophies of anarcho-primitivism, green anarchism, anti-civilisation, post-left anarchy, neo-luddism, and in particular the critique of technology. He rejects not only the state, but all forms of hierarchical and authoritarian relations. "Most simply, anarchy means 'without rule.' This implies not only a rejection of government but of all other forms of domination and power as well."

Zerzan's work relies heavily on a strong dualism between the "primitive" — viewed as non-alienated, wild, non-hierarchical, ludic, and socially egalitarian — and the "civilised" — viewed as alienated, domesticated, hierarchically organised and socially discriminatory. Hence, "life before domestication/agriculture was in fact largely one of leisure, intimacy with nature, sensual wisdom, sexual equality, and health."

Zerzan's claims about the status of primitive societies are based on a reading of the works of anthropologists such as Marshall Sahlins and Richard B. Lee. Crucially, the category of primitives is restricted to pure hunter-gatherer societies with no domesticated plants or animals. For instance, hierarchy among Northwest Coast Native Americans whose main activities were fishing and foraging is attributed to their having domesticated dogs and tobacco.

Zerzan calls for a "Future Primitive", a radical reconstruction of society based on a rejection of alienation and an embracing of the wild. "It may be that our only real hope is the recovery of a face-to-face social existence, a radical decentralization, a dismantling of the devouring, estranging productionist, high-tech trajectory that is so impoverishing." The usual use of anthropological evidence is comparative and demonstrative - the necessity or naturality of aspects of modern western societies is challenged by pointing to counter-examples in hunter-gatherer societies. "Ever-growing documentation of human prehistory as a very long period of largely non-alienated life stands in sharp contrast to the increasingly stark failures of untenable modernity." It is unclear, however, whether this implies a re-establishment of the literal forms of hunter-gatherer societies or a broader kind of learning from their ways of life in order to construct non-alienated relations.

Zerzan's political project calls for the destruction of technology. He draws the same distinction as Ivan Illich, between tools that stay under the control of the user, and technological systems that draw the user into their control. One difference is the division of labour, which Zerzan opposes. In Zerzan's philosophy, technology is possessed by an elite which automatically has power over other users; This power is one of the sources of alienation, along with domestication and symbolic thought.

Zerzan's typical method is to take a particular construct of civilisation (a technology, belief, practice or institution) and construct an account of its historical origins, what he calls its destructive and alienating effects and its contrasts with hunter-gatherer experiences. In his essay on number, for example, Zerzan starts by contrasting the "civilized" emphasis on counting and measuring with a "primitive" emphasis on sharing, citing Dorothy Lee's work on the Trobriand Islanders in support, before constructing a narrative of the rise of number through cumulative stages of state domination, starting with the desire of Egyptian kings to measure what they ruled. This approach is repeated in relation to time, gender inequality, work, technology, art and ritual, agriculture and globalization. Zerzan also writes more general texts on anarchist, primitivist theory, and critiques of "postmodernism".

In 1966, Zerzan was arrested while performing civil disobedience at a Berkeley anti-Vietnam War march and spent two weeks in the Contra Costa County Jail. He vowed after his release never again to be willingly arrested. He attended events organized by Ken Kesey and the Merry Pranksters and was involved with the psychedelic drug and music scene in San Francisco's Haight-Ashbury neighborhood.

In the late 1960s he worked as a social worker for the city of San Francisco welfare department. He helped organize a social worker's union, the SSEU, and was elected vice president in 1968, and president in 1969. The local Situationist group Contradiction denounced him as a "leftist bureaucrat". He became progressively more radical as he dealt further with his and other unions. He was also a voracious reader of the Situationists, being particularly influenced by Guy Debord.