The sitcom revolved around a girl who must learn to be responsible for her own actions. As she had the power of magic, she often used it to try to help her loved ones or herself, frequently resulting in literal puns that are often disastrous and always humorous.

The program began with Sabrina's adventures in high school in the fictional town of Westbridge, located near Boston, Massachusetts (as opposed to Greendale in the comics). In the series' later seasons, Sabrina graduated from high school and enrolled in college, then moved on to her attempts to live on her own and keep a job at the local newspaper. Breaking further from its comic roots, the show ended with Sabrina's wedding, although, in the end, she abandoned the wedding and ran off with Harvey.

Many episodes involve Sabrina getting to meet, through natural or supernatural means, popular real-life musical artists of the time, including Coolio, the Violent Femmes, the Backstreet Boys, Phantom Planet, Davy Jones of The Monkees, Britney Spears, Avril Lavigne, Daniel Bedingfield, Hanson, Eden's Crush, Savage Garden, 'N Sync, and Ashanti. Course of Nature, the band of Melissa Joan Hart's then-boyfriend (now husband) Mark Wilkerson, appeared in an episode in 2002.

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