The series centered on self-destructive Amy, who after experiencing a spiritual awakening, strives to live an enlightened life, creating chaos at home and work in the process.
Dern co-created the series with writer/director Mike White, and the actress won a Golden Globe for her role.
HBO issued the statement: "It was a very difficult decision...We're proud of the show and we look forward to working with Mike White and Laura Dern in the future."
Earlier this month, Dern tweeted about the show: "So excited to share our finale with you tonight. I feel honored to play Amy & be part of her finding her voice. We pray to explore more."
On March 4 she added, "Thank you everyone for the extraordinary outpouring of support and love for Enlightened. We're so grateful."