Cannery Row is difficult to summarize accurately given its shifting chronology and the occurrence of inter-chapters that are unrelated to the main narrative, but the general outline of the novel is as follows:
Lee Chong, the main grocer of Cannery Row, agrees to allow Mack and his group of itinerant men to reside in an old warehouse he has acquired. Mack and his boys move in and christen their new place the Palace Flophouse and Grill. They fix it up and feel prideful of their home.
Near the Palace Flophouse is Dora’s Bear Flag Restaurant, a cheerful and well-run brothel. The watchman at Dora’s is Alfred, who took over after the last watchman committed suicide in a fit of despair. Across the street from Dora's is Western Biological, the laboratory belonging to Doc, a wiry and bearded scientist. Everyone on Cannery Row likes Doc and thinks about doing nice things for him.
Doc and one of Mack’s boys, Hazel, collect specimens in a tide pool. Hazel tells Doc that another man is coming to stay at the Palace Flophouse – Gay, who fights with his wife a lot and goes in and out of prison. Back at the Palace, the boys discuss doing something nice for Doc and light upon the idea of throwing him a party.
Mack knows that they need money to throw the surprise party, so he asks Doc if he has some work for them. Doc is wary, knowing that Mack can be untrustworthy, but he needs frogs to fulfill an order. He tells Mack that he will pay him a nickel per frog. However, Mack and his boys will need to drive to find the frogs, so he asks Lee Chong for his truck. Lee Chong agrees to let Mack borrow the truck after Mack promises that Gay, who is a gifted mechanic, will fix it up.
There is a young boy named Frankie who hangs around Doc’s lab. Frankie no longer goes to school because he has trouble learning and with coordination. He takes a liking to Doc, who lets him help out around the lab. Frankie grows to love and respect Doc and is always eager to impress his mentor. Frankie is clumsy though, and embarrasses himself by dropping a tray of drinks on a friend of Doc’s. After that, Frankie is inconsolable.
Meanwhile, Mack and the boys prepare for their expedition. Gay fixes up Lee Chong's truck and they start on their journey. At one point, the truck breaks down and Gay leaves to find a part for it, but he does not return. It turns out that he ended up in a Salinas jail after a random and unlucky series of events. After some time, another member of the gang, Eddie, manages to find the part, and the journey continues.
On the night of their frog hunt, Mack and the boys camp out on a piece of land. However, a man approaches them and tells them that they must leave immediately. Mack, a seasoned sweet-talker, befriends the man, whom they call "the Captain." The Captain invites the boys in for a drink and then gives them permission to gather frogs on his pond. He also gives Mack a puppy to take home.
While Mack and the boys are on the frog-collecting trip, Doc drives down to La Jolla to collect baby octopi. He stops many times along the way for food and drink, picks up a hitchhiker, and then discards him when he says Doc ought not to drive drunk. Doc then goes to a diner orders a beer milkshake from a surprised waitress just to see what it tastes like. He proceeds to the tide pools and gathers his specimens, but is disturbed when he peers off the edge of the reef and sees the floating body of a dead girl in the water. He cannot get her face out of his head.
Back in town, Mack and the boys trade frogs for party supplies at Lee Chong’s, telling Lee that he can sell the frogs to Doc for money. They have planned to throw Doc's party that night, as they are expecting Doc to return. The boys gather at Doc's laboratory and the festivities begin. However, Doc does not return until the following morning, by which time the party is over. Furthermore, all of the frogs have escaped.
When Doc gets back to his lab, it is utterly destroyed. His precious records are smashed, windows are broken, and greasy dishes are piled high. Mack meekly apologizes, but Doc pummels him in anger. Mack refuses to fight back, knowing that he deserves it, and Doc relents. He pours Mac a beer and, with a sigh, asks him what happened.
Mack and the boys become outcasts after the party debacle, and all of Cannery Row sinks into a malaise. Everyone is miserable, tired, and prone to fighting or issues with their businesses. The boys' beloved puppy, whom they have named Darling, falls ill. They have to ask Doc to help her out, which he does coolly but willingly. Doc does not hold a grudge against Mack and the boys, and muses to his friend that they are the most philosophical men in Cannery Row.
Doc's advice proves to be helpful and Darling quickly recovers. After that, things slowly begin to improve around the Row. Mack asks Dora what he should do to make it up to Doc, so she suggests throwing a party that Doc can actually attend.
Thus, plans are in place for another party, this time on Doc’s birthday (although Mack does not realize that Doc gave a false date when Mack asked about his birthday). All of Cannery Row knows about the party except for Doc, who forgets that he gave Mack a made-up birthday. Everyone comes up with heartfelt and homemade presents for Doc. Frankie loves Doc so much that he tries to steal an expensive clock to give him, but in the process, he is captured by the police and sent to a mental institution because it is assumed that his lack of intelligence and criminal proclivities will make him a danger to society once he hits puberty.
Doc does eventually hear about the planned party from a random drunk at a bar, and he decides to forestall some of the problems from the first celebration by buying alcohol and food and locking up his cherished and/or breakable possessions.
The night of the party arrives, and it begins slowly but then it soon blossoms into a lively, fun, and boisterous affair with fights and food and dancing. Doc even reads a poem to the crowd that renders them pensive and nostalgic for lost loves.
The next morning, Doc cleans up, hearing music in his head and reciting lines from the poem again.