The Weeds season 5 debut attracted 1.2 million viewers, with a rerun on the same night adding another 500,000 viewers for a cumulative 1.7 million. In season 5, Silas was 18 and Shane was 14. After Nancy informs Esteban that she's pregnant, he allows her to live but has bodyguards assigned to her and forces her to undergo a chorionic villus sampling to be sure the baby is a boy and his. Anxious for her Shane's safety, Nancy has Andy take him to her sister, Jill Price-Grey (Jennifer Jason Leigh). In the later episodes, Jill arrives back with Shane and Andy. Jill explains that Shane took pictures on his phone of her having sex with Andy. Meanwhile, Silas draws up a new plan to start a legal medical marijuana business, which Nancy funds. The bodyguard mysteriously disappears and Nancy panics because he was probably murdered.

Quinn's attempt to extort money from Celia's family or friends fails, since none of them are willing to pay any ransom, and her later plan to kill Celia and sell her organs doesn't pan out due to her having had cancer. This leads to an internal dispute between Quinn and Rudolfo, and their relationship ends. Celia tries to get Rudolfo to let her stay with him but he drugs her and puts her on a bus to Texas. With nowhere else to go, she ends up squatting in Nancy's garage, where she finds the body of the missing bodyguard. The new bodyguard catches DEA agent Captain Roy Till and Nancy calls Esteban, who has Till killed. Andy suggests that he and Nancy have an abortion and flee with US$180,000 he found in Judah's old bank account, because she will never be free if she has a baby with a Mexican drug lord. Nancy instead leaves a note for Andy, saying she, Shane, and Silas have moved in with Esteban.

Six months later, Esteban proposes to Nancy and she accepts, but Pilar (Kate del Castillo), a powerful woman in Mexican politics, forces Esteban to break off his engagement to Nancy. Cesar, Esteban's chief aide, arranges a birthing room in the house, so there will be no record of the baby's birth. Escaping Esteban's house with Andy's aid, Nancy gets to her obstetrician, Dr. Audra Kitson (Alanis Morissette), who takes her to the hospital and delivers the baby. To protect his political career, Esteban will not sign the birth certificate. Nancy moves back in with Andy, who agrees to sign the birth certificate, hoping she'll free herself from Esteban; he also gets Nancy to give the baby a Bris, much to Esteban's dismay.

Shane witnesses violence at the hands of Esteban's bodyguard. He continues to sell pot at school and when a teacher steals a bunch of product, Shane reacts violently. Shane goes to the teacher's apartment with Isabelle and Esteban's bodyguard and kills the teacher's pet bird with a gun.

Esteban wants to see his son and comes to Nancy's door to ask her to marry him again. Simultaneously, an assassin trying to kill Nancy accidentally shoots Shane in his left shoulder. Nancy confronts Cesar, who admits that he has been an informant for Pilar, who arranged the assassination, of which Nancy was the intended target. The hit was not completed because Cesar could not bring himself to do it. Nancy keeps the betrayal from Esteban in exchange for shooting Cesar in the arm, like Shane had been. Esteban finds himself replaced as a candidate for governor, but with encouragement from Nancy, he runs as an independent.

Silas and Doug's shop is having problems; as Doug keeps eating their products, he is stoned all the time, and does not keep up his work responsibilities. The policeman in their pay begins demanding more money or he will cause them troubles. But then, they are raided by a sting set up by Internal Affairs against the cop, and they lose all of their pot. They go to Dean to help them get it back. Meanwhile Celia, who had been working in retail at the mall, gets a job as a cosmetics seller for a Mary Kay-like company. Unable to sell the products, Celia gets Dean to give the pot to her and starts selling it packaged with the cosmetics.

Doug finds out that Celia stole their pot and he and Dean plot revenge. After Shane is unexpectedly shot in the arm, Shane eschews painkillers, saying he prefers the pain. Instead, he begins drinking alcohol—sneaking it from the refrigerator as desired. Silas refuses to go abroad to study, expressing worry that Shane is going to "crack up".

Andy begins a relationship with Audra, with the family moving into Esteban's house, as Nancy and Esteban get married at home. Nancy visits Guillermo in prison to have him arrange the assassination of Pilar in exchange for Nancy getting Guillermo extradited to Mexico. Esteban becomes the front-runner for governor despite Pilar's rejection, but he is arrested in Mexico for suspicion of conspiracy, racketeering and tax evasion. Nancy and Cesar go to get Esteban from jail, but they find out on national television that Esteban had been already released and is rerunning for governor. Pilar had had him arrested and is blackmailing him into joining her ticket and becoming her puppet in exchange for being freed, while letting Esteban free despite the evidence Pilar has on him. Pilar confronts Nancy and tells her that she and Esteban must do everything Pilar dictates. Andy announces that he is going to propose to Audra, with his mother's ring, previously given to Nancy by her late husband Judah. Nancy is upset and initially refuses to give Andy the ring, but later relents.

Thereafter, Celia gathers Doug, Dean, Sanjay, Ignacio, and Isabelle—teaming them up to sell marijuana in a deliberate echo of season one when Nancy did the same. Pilar discreetly, but forcibly, escorts Nancy from a fund-raising party. As they walk by a pool on the outside deck, Pilar reveals to Nancy that she was aware of her actions. Pilar then suggests that the unfortunate deaths of Shane and Silas, appearing to be accidental, would generate a sympathy vote for Esteban. Nancy then warns Pilar that she will kill her if she takes such attempts toward her children. Without warning, Pilar is hit in the head by an unseen third party and ends up floating face down in the pool bleeding profusely from the head. Shane appears next to Nancy, holding the croquet mallet he just used to murder Pilar.

The fifth season finale episode premiered on Monday, August 31, 2009, averaging 1.3 million viewers, up versus season 4's finale that averaged 1 million.