Sheldon and Amy are surprised to find that Wil Wheaton's new Professor Proton show is actually very entertaining and that Wil had Howard on as a guest. On Howard's suggestion, Sheldon apologizes to Wil, mending their friendship, and tells him he wants to be on the show; but Wil asks for Amy. Sheldon tells her to do it, but she says she often doesn't do things to avoid upsetting him. Sheldon is horrified when he realises how selfish he has been, especially when he finds out that the men do the same for him. Sheldon encourages Amy to go on the show to inspire girls to pursue science while trying to control his obvious jealousy for her. Meanwhile, Leonard writes a book about a physicist that solves a murder, the protagonist Logan Dean is based on himself. Bernadette points out Logan's mean boss Illsa is similar to Penny, who thinks it is based on Bernadette, though Leonard does not correct her. However, Bernadette tells Penny the truth, upsetting her and making her mad at Leonard. After calling his mother for advice, Leonard learns that Illsa is actually like her; but abandons the book when he realizes he wrote romantic tension into the relationship between the characters.
In March 2017, CBS renewed the series for two additional seasons, bringing its total to twelve, and running through the 2018–19 television season. On August 22, 2018, CBS and Warner Bros. Television officially announced that the twelfth season would be the series' last. This stems from Jim Parsons' decision to leave the series at the end of the season if the show were to have been renewed for a thirteenth season. The series concluded with an hour-long finale consisting of two back-to-back episodes on May 16, 2019. A retrospective, hosted by Johnny Galecki and Kaley Cuoco, aired at 9:30 P.M. ET/PT, the night of the finale, following the season two finale of Young Sheldon.
Two physicists from Chicago, Dr. Campbell and Dr. Pemberton, accidentally prove Sheldon and Amy's super-asymmetry theory. This puts them on track for a Nobel Prize, but Leonard points out they tend to go to the experimental scientists who prove a concept instead of theorists like Sheldon who come up with it. Meeting with them, they tell Sheldon they are willing to share the Prize but only three names can be on the submission, and they want to cut Amy out. Amy does not want to prevent Sheldon's lifelong dream, but he goes to President Seibert who agrees to fight for Amy on their behalf. Meanwhile, Bernadette's drug has been approved and she wants to promote Penny to lead the marketing team. Penny resists, knowing Bernadette's attitude at work and doubting her own inexperience to take the responsibility, but Bernadette uses reverse-psychology to get Penny to take the job. Penny mirrors Bernadette's commanding style to get the other employees in line, impressing Bernadette.
After Sheldon reminds the guys about the time they mined Bitcoin without him, the guys go on a quest to find their suddenly valuable missing cryptocurrency. They realize the currency is on a laptop which Leonard gave to Penny when they dating, which she then gave to her ex-boyfriend Zack. After Leonard and Penny go to Zack's apartment, he shows them a seven-year-old video that Penny recorded on the laptop soon after she broke up with Leonard. Leonard is touched by the video which shows a drunk Penny lamenting the break-up of her relationship with him.