Cheryl and Betty met at some point before the start of the series. They share a connection, as Cheryl's now deceased twin brother Jason dated Betty's older sister Polly, and apparently, their relationship did not end on good terms. After her brother's death, Cheryl started to despise Betty and continuously humiliate her whenever she got a chance.
During the previous school year, Betty tried out for the cheer squad but was rejected by Cheryl who claimed Betty was too fat.
When Veronica Lodge moved to Riverdale and enrolled at Riverdale High School, she befriended Betty and managed to convince her to join the River Vixens cheer squad, which was run by Jason's sister, Cheryl Blossom. When Betty and Veronica failed to impress Cheryl, she put Betty in an uncomfortable spot in which she was forced to explain her sister's mental heath in front of the entire cheer squad and Veronica, causing Betty to self-harm by clawing at her hand with her nails so as not to be provoked. However, Veronica managed to save her new friend by telling Cheryl that they came as a package deal, otherwise Veronica would refuse to join, and Cheryl reluctantly accepted and allowed both Betty and Veronica to join the River Vixens. However, Cheryl took delight in tearing Betty and Veronica's burgeoning friendship apart at her party later that night. Cheryl manipulated Veronica into playing Seven Minutes in Heaven with Archie Andrews, who she knew Betty had feelings for. Betty left the party in distress.
Cheryl took advantage of this situation and feigned being nice to Betty and offering herself as an alternative friend. She went round to her house and pretended to be apologetic about her past treatment of her, but was really digging for information about Polly. It was revealed that she believed Polly had killed Jason, and so Betty forcefully told Cheryl to leave her house before she killed her.
Cheryl encountered Betty and Veronica plotting to take revenge on certain members of the football team for slutshaming them. When told they had a book listing their conquests, she was disbelieving, certain that Jason would have told her about it if it was true. When they stole the book, though, she discovered that Jason had not only known about it but had participated, as Polly Cooper's name was listed in the book. This forced her to reevaluate her opinion of her brother, and she apologized to Betty for his actions and they burned the book together.
After Polly Cooper's escape from the Sisters of Quiet Mercy group home, and an unsuccessful search for her, Alice Cooper held a press conference and, much to Cheryl's surprise, revealed to the entire town that Polly was pregnant with Jason's child. Polly was eventually found by Betty, hiding in the attic of the Cooper house, where she revealed that their parents were trying to for her to give the baby up for adoption. Betty was speaking to Veronica in the student lounge the next day about Polly's situation when they were were interrupted by Cheryl, who wished to help Polly and the baby. Reluctantly, Betty revealed that she knew where Polly was and that she needed money for a place to live and medical supplies, to which Cheryl responded that her parents would be more than willing to help.
That night, Betty met up with Cheryl and her parents at Pop's Chock'lit Shoppe, where they assured Betty that they could assist Polly with emotional and financial support, all Betty had to do was trust them enough to tell them where Polly was. They were set to meet again the next night, however, Cheryl came alone to warn Betty and Polly of her parent's ill intentions; they did not care about Polly, they just wanted the baby. Cheryl told Betty and Polly to leave, before her parents arrived.
With Polly living with the Lodges at The Pembrooke, Jughead, Betty, Cheryl, Archie, Veronica, Kevin and Valerie analyzed Polly's dilemma, in which the Coopers wanted her but not the baby, and the Blossoms wanted the baby, but not her. Veronica suggested that they throw Polly a baby shower, which would force the Coopers to finally start communicating, which Cheryl was in full support of.
On the night of Polly's baby shower, Cheryl came bursting through the front door of Hermione's apartment with a brand new, expensive stroller for Polly and Jason's child. All Cheryl asked for in return was that she be named the baby's godmother, unaware that Polly had earlier named Betty the godmother. A little later in the night, as Polly opened the gifts, Cheryl expressed her desire for Polly to stay with them at Thornhill, which Cheryl's mother assured Polly was a genuine offer. However, this started an argument between Penelope Blossom and Alice Cooper. Cheryl stepped in in support of her mother, but Betty quickly rebuked her as she was not helping the situation. After the shower, Polly decided to go live with the Blossoms.
After attempting to contact Polly to no avail, a brief confrontation took place between Betty, Jughead and Cheryl, in which Betty demanded that she be allowed to talk to Polly. Cheryl told her they shouldn't be fighting but celebrating as she revealed that a doctor confirmed Polly was expecting twins, which Betty was unaware of. She was shocked to learn that her own sister did not tell her, but she pleaded with Cheryl to at least deliver a message, for Polly to call their mother as she missed her, despite her best efforts to hide it. Cheryl agreed to pass on the message but made no promises that Polly would care or respond.
Betty comforted Cheryl about her feelings of the nightmare not really being over. When Betty found out that Clifford Blossom is Jason's killer, she immediately called Cheryl and told her to get out of Thornhill.
Cheryl: "Tell Veronica about your sister and my dear brother."
Betty: "Polly and Jason dated."
Cheryl: "'[scoffs] I wouldn't say "dated"."
Betty: "It didn't end well."
Cheryl: "In fact, Jason's probably why your sister had a nervous breakdown and now lives in a group home, isn't it?"
Betty: "That's what my parents think."
Cheryl: "What do you have to say about that, Betty? Go ahead, the floor is yours. Whatever you've been dying to spew about Jason and how he treated Polly, unleash it. Destroy me. Tear me a new one. Rip me to shreds. Annihilate me."
Betty: "I just..."
Betty: "I just wanted to say I'm sorry about what happened to Jason. I can't even imagine what you and your family must be going through."