Cannery Row is a book without much of a plot. Rather, it is an attempt to capture the feeling and people of a place, the cannery district of Monterey, California, which is populated by a mix of those down on their luck and those who choose for other reasons not to live "up the hill" in the more respectable area of town. The flow of the main plot is frequently interrupted by short vignettes that introduce us to various denizens of the Row, most of whom are not directly connected with the central story. These vignettes are often characterized by direct or indirect reference to extreme violence: suicides, corpses, and the cruelty of the natural world.

The "story" of Cannery Row follows the adventures of Mack and the boys, a group of unemployed yet resourceful men who inhabit a converted fish-meal shack on the edge of a vacant lot down on the Row. Mack and the boys want to do something nice for Doc, the proprietor of a biological supply house on the Row who is a gentle and intellectual man and a friend and caretaker to all but who always seems haunted by a certain melancholy. They plan to give Doc a party and spend a good deal of energy acquiring provisions for the party in the process alternately enriching and enraging Lee Chong, the local grocer.

They set up in Doc's lab (which doubles as his living quarters) one night while he is gone on a specimen-collecting trip, and the party begins while they wait for him to return. Doc is late in getting back, though, and when he drives up at dawn the party is over and his place is completely trashed. A bad feeling pervades the Row for a long time after the party, and an influenza epidemic and several other unfortunate events occur. Finally the tide of luck changes, and the inhabitants of the Row start faring a little better. Grateful to Doc for curing their sick puppy, Mack and the boys again decide to do something nice for him. Following the advice of Dora, the local madam, they fix on another party, this time a party that Doc can actually attend. Chastened by their first failure, the boys are much more careful with the planning and execution this time around. The party is a great success. The novel ends the morning after the party with Doc cleaning up his home and reflecting on life.