Several months after getting married, Mollie and James welcome their second child, Mikey's half-sister Julie into the family. While at first, Mikey is excited to be a big brother, he begins to resent his sister shortly after she is born when the reality does not match what he dreamed being a big brother would be like. In turn, Julie is not impressed by Mikey, who also struggles with potty training, having several accidents despite encouragement from his friends and family. James, who was provided a job as a full time pilot thanks to Mollie's parents, and Mollie begin to struggle with their lack of time together straining their relationship. Mollie's younger brother Stuart comes to live with them temporarily, and James is hesitant, especially when Stuart pulls an (unloaded) gun on him thinking he's an intruder. The arguing between Mollie and James grows in intensity until James walks out, believing Julie is responsible for the situation, Mikey takes his vengeance out on Julie's stuffed bird Herbie. Meanwhile, after her apartment is robbed, Mollie's friend Rona comes to stay with them, and she begins to date Stuart.
During one of James' visits, where he takes Mikey and Julie out to the movies, sneaking them in and getting them popcorn for free, he spends the day with them and this makes Mikey realize that he may have been too hard on his sister. Later, when Julie decides she doesn't need Mikey and wants to strike out on her own, she is inspired to walk unsupported. Mollie sees this and showers Julie with affection for her accomplishment, the happiness is short lived however, as James is not there to share the moment. James returns home to talk to Mollie and Mikey accomplishes going to the bathroom on his own, which is a celebration both of them share with him. James is due to go flying and with a massive storm building in the area, Mollie gets worried and leaves Mikey and Julie in Stuart's care. While she is gone, a robber sneaks into the apartment and Stuart scares him out with his gun. Forgetting that Mikey and Julie are in the apartment, Stuart gives chase, leaving the stove on, which then catches some paper he left on the stove on fire that begins to spread quickly through the apartment. Thinking quickly and calmly, Mikey manages to push Julie out of harm's way.
Meanwhile, James and Mollie returning home from her stopping him from taking off during the storm return to intervene and subdue the burglar that Stuart is chasing. Momentarily panicked seeing fire in the apartment, Mollie and James are relieved as Mikey exits the elevator with Julie in tow. James runs to the apartment and puts out the fire before any major damage is caused and the day is saved. Later, at a barbecue with James, Mollie, Rona, Stuart and Mollie's parents, Julie and Mikey have a conversation on how strange the adults are, and how much they are needed in their lives. Julie agrees and the two walk off together hand in hand.
John Travolta as James Ubriacco/Voice of James' sperm cells (uncredited)
Kirstie Alley as Mollie Ubriacco (nee Jensen)/Voice of Mollie's egg (uncredited)
Lorne Sussman as Mikey Ubriacco
Megan Milner as Julie Ubriacco (age 1 year)
Georgia Keithley as Julie (age 4 months)
Nikki Graham as Julie (fetus–newborn)
Danny Pringle as Eddie
Elias Koteas as Stuart Jensen
Twink Caplan as Rona
Olympia Dukakis as Rosie Jensen
Lesley Ewen as Debbie
Gilbert Gottfried as Joey, the baby gym instructor
Don S. Davis as Dr. Fleischer
Bruce Willis as Mikey Ubriacco
Roseanne Barr as Julie Ubriacco
Damon Wayans as Eddie
Mel Brooks as Mr. Toilet Man
sequel to Look Who's Talking, and the second installment in the titular franchise