Dan Schneider first met Jamie Lynn Spears for an audition in 2002 when she was 11 years old, after a Nickelodeon executive suggested he meet Britney Spears' younger sister.

The series was created as a custom-made star vehicle for Jamie Lynn Spears, similar to how Kenan & Kel and The Amanda Show were built around their stars, and her mother Lynne reportedly had a lot of input on the show.

Jamie Lynn Spears recalled that her first meeting to discuss the show took place at Houston's restaurant in Santa Monica, where she insisted Zoey have a tomboy side and be strong and confident, reflecting her own personality at age 11 or 12.

Actress Erin Sanders originally auditioned for the role of Nicole, but the part went to Alexa Nikolas instead; Dan Schneider then created the character of Quinn Pensky specifically for Sanders.

Kristin Herrera left the show after season one and was replaced by Victoria Justice, while Sean Flynn departed after season three (citing a wish to focus on his education) and was replaced by Austin Butler.

Alexa Nikolas left the series after season two following numerous conflicts with Jamie Lynn Spears, including a confrontation in which Britney Spears reportedly screamed at Nikolas, calling her an 'evil little girl.'

Zoey 101 was Nickelodeon's most expensive production ever at the time because it was filmed entirely on location at Pepperdine University in Malibu for its first two seasons, with the university reportedly paid $350,000 for season one and $500,000 for season two.

For season one, two student lounges in Pepperdine's Rockwell Towers were converted into dormitory sets, and filming had to be scheduled between 10 a.m. and 10 p.m. to accommodate students and minimize disruption.

Starting with season three, production moved to the Mann Biomedical Park in Santa Clarita Valley, a business park built by Lockheed to resemble a college campus, where a hilltop parking lot was used to simulate an ocean view for the beach scenes.

The series finale 'Chasing Zoey' became the highest-rated live-action show ever on Nickelodeon with over 7.3 million viewers, also beating American Idol in the 12–17 demographic that week.

Jamie Lynn Spears' real-life pregnancy, revealed in December 2007 while the already-completed fourth season was airing, sparked controversy among parents, though Nickelodeon decided not to cancel the season, and a planned Nick News episode addressing teen pregnancy was quietly cancelled.