An abandoned waif and her dog are taken in by a cranky apartment manager who becomes her guardian in this family-friendly sitcom.
Punky and Cherie must get back an urn that contains the ashes of Henry's late aunt Mable, after Punky and Cherie give the urn away to a convent without knowing what's in the urn.
Punky has a crush on 16 year old Kevin Dowling, who is helping Punky install a stereo in the treehouse. Punky tells Henry about Kevin, and Henry, who doesn't understand that Punky has a crush on Kevin, vows to break every bone in Kevin's body. Punky is crushed when she meets Kevin's girlfriend Gina.
Punky, Cherie, and Margaux go to summer camp, where they learn about such traditions as T-shirt raids, and the kissing rock, but Punky doesn't seem to have the same romantic visions about these things that Cherie, Margaux, and their roommate Marcie have -- until Punky is kissed by a boy named Jimmy. Also, Cherie is annoyed by Franco Grenolli, a fellow camper who has a crush on her.
When Margaux and her parents go bankrupt and auction off all of their belongings, Punky and Cherie use their skiing trip money to buy Margaux's favorite doll back for her -- a true showing of friendship that Margaux dearly appreciates. Margaux returns the favor by repaying Punky and Cherie's skiing trip money when her family comes back into having mega money again.
Brandon gets a shot at stardom when Churchill,the famous dog hired for a dog food commercial to be filmed at the restaurant, gets camera shy -- and so does Brandon, blowing a chance for $1000 and also messing up Punky's dream of Brandon becoming a star, and for this, Punky calls Brandon a bad dog. After Henry helps Punky realize that she was the one who wanted to be a star, Punky apologizes to Brandon.
While Henry is in Detroit buying supplies for the restaurant, Punky and Cherie decide to run the restaurant, and they panic when a customer named Ralph falls asleep because of narcolepsy. Punky and Cherie don't realize that Ralph is just asleep. They think Ralph is dead because of the secret ingredient Cherie uses when she makes hamburgers.
Punky wants to give Henry a pocket watch for Christmas. When rich businessman Horatio Lake is robbed of a briefcase just before Christmas, Punky solves the robbery and figures out that Mr. Lake's son Jerry Lake is the thief. Punky tells Mr. Lake what went on -- Jerry had a plan. Jerry figured he would take the briefcase and lay low with it for a few days, then when the police gave up, Jerry would say that he found the briefcase. That way, Jerry would be the hero, and maybe, just maybe, Mr. Lake would pay more attention to Jerry, who wanted attention from Mr. Lake after years of being ignored by Mr. Lake. Mr. Lake wonders how he could've let things get to a point where Jerry thought he had to do what he did. Mr. Lake realizes his mistake of ignoring Jerry all these years, and he vows to not let that mistake happen again. As a reward to Punky for solving the robbery and helping Jerry and Mr. Lake become closer than ever, Mr. Lake gives Punky a pocket watch, and Punky gives it to Henry as
Punky and Cherie sell cosmetics door to door for Lady Contempo Cosmetics, until they discover that Lady Contempo Cosmetics is a scam run by a con artist named Sidney. Henry washes his hair with Lady Contempo shampoo and wakes up the next morning with no hair on his head. Punky and the gang have to deal with angry customers who have also felt the various side effects of Lady Contempo products, and when they go to Lady Contempo to confront Sidney, they see that Sidney has cleared out, and it turns out that the reason why Henry is bald headed is because he washed his hair with Contempo furniture stripper that Sidney had disguised as Lady Contempo shampoo, and the reason why the blue face mask won't come off of Betty's face is because the face mask is actually kitchen floor wax that was disguised as the face mask cream. While they are in Sidney's office, A detective named Denko shows up looking for Sidney, who has cleared out.
One of Betty's favorite patients dies and leaves her a Texan car with big bull horns on its hood, but Betty doesn't know how to drive. Henry's attempts to teach Betty how to drive result in Betty crashing the car into a tree, and because of this, Henry and Betty decide to sue each other, and it's Punky and Cherie who help Henry and Betty put aside their differences and be friends again.
Punky and Cherie enter a radio scriptwriting contest sponsored by a local radio station that has just changed its format from rock music to radio stories, and Punky, Cherie, and Margaux hope to win the grand prize trip to Disneyland, unless their opponents Garth Goobler and Grant Goobler, the self centered sons of a radio star, stand in their way. Punky, Cherie, and Margaux outdo the Goobler brothers and win the contest.
Cherie's aunt Larnese, who is Betty's sister, arrives for a visit on Cherie's 12th birthday, and asks Cherie if Cherie would like to live with Larnese in Paris, France.
A nosy Punky sneaks a peak at Cherie's diary, and Punky is shocked to see that Cherie has written unkind things about Punky in it.
Cherie's cousins Paula and Bobby arrive for a visit, and Paula, who doesn't know how to read, can't read the warnings and help messages on a bottle of fabric softener that Bobby drank out of.
Punky is terrified when she has to have her appendix removed, and angry when it delays the vacation that Punky, Cherie, Brandon, Betty, and Henry were getting ready for when she collapsed from the pain of appendicitis.
The apartment building's new owner -- Margeaux's father Benjamin J. Kramer -- wants to increase Betty's rent by 60%. Betty is afraid that a 60% rent increase would force her and Cherie to move out of the building.
Punky and the gang want to know why Brandon is acting so strange lately, then Brandon is accused of biting a new neighbor, Ms. Jenner, and as a result, Ms. Jenner wants Brandon to be put to sleep (euthanize), so Brandon is taken to an animal shelter for examination.
When Punky is grounded, she has a dream that she is an indulgent parent who lets her kids do whatever they want to do.
Cherie thinks she's a wimp after failing to prevent Punky from falling out of the treehouse, and Punky suffers a broken leg as a result. Cherie later regains her courage in a stalled elevator at the hospital with a pregnant woman named Nancy, who goes into labor.
Punky's new math tutor Walker Wimbley turns out to be a Casanova who tests the friendship between Punky and Margaux by falling head over heals for Margaux -- crushing a lovestruck Punky. Walker turns out to be a jerk, and with Margaux and Cherie's help, Punky gets even with Walker.
Punky is in a mess when she ends up having to juggle two dates -- Brian and Tom -- at the Saturday afternoon movie, and Cherie carries a camera around with her and takes pictures of how Punky, Brian, and Tom deal with it.
During a firefly girl troop meeting, Punky befriends a deaf girl named Maria Aragon, and Maria begins to think that because of her disability, she'll never be accepted by the other girls, so Punky helps Maria make friends in the troop.
In the final episode of Punky Brewster: Punky and the gang throw a wedding for Brandon and another golden retriever named Brenda, who is owned by Punky's friend Myron. As Punky and the gang prepare for the wedding and the wedding takes place, there are flashbacks, focusing on some of Brandon's scenes from past episodes.