The network said about 16.2 million viewers tuned in to see the show's final installment.
Former cast members Noah Wyle, Eriq La Salle, Sherry Stringfield, Laura Innes and Alex Kingston made special appearances during the two-hour series finale, which opened with the show's original music and montage from Season 1.
The finale, which concluded with the hospital staff rushing to care for victims of an explosion, also featured a visit from beloved dead character Dr. Mark Greene's now-adult daughter, who is hoping to follow in her dad's footsteps.
Greene's portrayer, actor Anthony Edwards, was seen in newly taped flashbacks this season.
Original cast members George Clooney and Julianna Margulies also returned for a special episode several weeks ago to say goodbye to the show that helped launch their careers.
The "ER" finale earned the biggest viewing audience for any drama closer since 16.5 million people watched "Murder, She Wrote" end in 1996, NBC said.