At Fashion Interpol, Valentina Valencia (Penélope Cruz) investigates the final images of pop stars who have been murdered, noting that they bear an unsettling resemblance to Derek Zoolander's (Ben Stiller) iconic expression, "Blue Steel." The latest victim, Justin Bieber, who met his demise proclaiming, > "You can't kill us all, we will protect the chosen one," adds to the mystery. In a poignant flashback, we see the tragic collapse of the Derek Zoolander Center for Kids Who Can't Read Good, which resulted in the death of Matilda Jeffries (Christine Taylor) and the injury of Hansel McDonald (Owen Wilson). Following this devastating event, Derek loses custody of his son, Derek Zoolander Jr. (Cyrus Arnold) and retreats from the modeling world, isolating himself in "extreme northern" New Jersey.
Life takes a turn when Billy Zane brings an invitation from Alexanya Atoz (Kristen Wiig), the head of a leading fashion empire, urging Derek to return to the limelight to reclaim custody of his son. Meanwhile, in the "uncharted Malibu territories," Hansel is informed by his orgy that he is about to become a father. Together with this unexpected news, he too receives Zane's invitation. Upon their reunion, Derek and Hansel are approached by Valentina, who seeks their assistance in solving the string of murders plaguing the pop culture scene. Derek enlightens her that the likeness on the deceased stars is not merely "Blue Steel," but rather the lesser-known "Aqua Vitae" from a 90's campaign, sporting the tagline "Young Forever."
During the fashion show, both Derek and Hansel are shocked to discover a bizarre evolution in the industry, now led by Don Atari (Kyle Mooney) and the androgynous All. Clad in "Old" and "Lame" attire, they are embarrassingly drenched by a cascade of prunes, only to receive unexpected praise from Alexanya post-performance.
Valentina guides Derek to discover that his son resides in a local orphanage, where he is heartbroken to see Derek Jr. struggling with obesity. A ghostly plea from Matilda moves Derek to accept his son, but after a brief outing in Rome, their bond falters, leading Derek Jr. to retreat to the orphanage. Hansel receives a mysterious call to meet at St. Peter's Basilica at midnight, where he, Derek, and Valentina encounter Sting, who weaves the tale of Adam, Eve, and the lesser-known Steve, the alleged ancestor to all models, linked to the legendary Fountain of Youth.
When Derek's attempts to locate Derek Jr. lead him to a neglected orphanage, Valentina conducts facial recognition scans, revealing a connection between the orphanage's headmaster and Jacobim Mugatu (Will Ferrell). As he makes his way to confront Mugatu, Derek is captured, allowing Mugatu to make his escape by helicopter, while Hansel cleverly stows away on top of the aircraft.
In a race against time, Derek and Valentina swim back to Rome as Hansel infiltrates the House of Atoz. There, he discovers Mugatu's sinister plans as he plots to kill Derek Jr. to consume his heart, believing it will grant them eternal youth. With Valentina and Hansel, Derek intercedes just in time to thwart Mugatu's gruesome intentions. The coalition of designers, spurred by revenge against Derek, rapidly descends into chaos as the fatal encounter unfolds.
Upon hurling a powerful explosive back at Mugatu, Derek's destiny shifts, leading to reconciliation with Derek Jr. and a love confession with Valentina. Matilda's spirit grants her blessing amidst the turmoil, echoing that the entire event was streamed live.
Fast forward six months, and the world of modeling sees a resurgence with both Derek and Hansel back in action. Derek and Valentina celebrate their new life together with a daughter, Darlene, while Derek Jr. embarks on a romantic journey with Malala Yousafzai. Meanwhile, Hansel embraces his bohemian lifestyle as a devoted father of ten.
