Friends and roommates Leonard and Sheldon, theoretical physicists with social issues, meet their attractive new neighbor, Penny, who is their complete opposite.
In an attempt to impress Penny, Leonard offers to accept a package for her. However, he brings in the obsessive-compulsive Sheldon, who becomes desperate to clean her apartment, which angers Penny.
When Leonard learns that Penny is seeing someone else, he becomes depressed. Thus, with the support of his friends and other scientists, Leonard makes the brave decision to ask a woman out.
Sheldon tries to learn more about life outside of physics after losing his job. But the excitement of shopping with Penny quickly turns into him making ponchos, which makes Leonard call Sheldon's mother.
Leslie Winkle, a fellow scientist, and Leonard agree to an unexpected sexual meeting in an attempt to get over Penny. But when he finds out that she was only looking for a one-night stand, he is disappointed.
Leonard, Sheldon, Howard, and Raj are invited to Penny's Halloween party, putting their social skills to the test once again. Leonard plans to get closer to Penny, but his goals change when Penny's ex-boyfriend, Kurt, shows up.
Penny asks to sleep on Leonard and Sheldon's couch at their home after Howard seduces her friend and they spend the night together at Penny's place. After realizing how much they depend on Howard, Leonard, Sheldon, and Raj try to find a way to win him back.
When his parents set up a blind date for Raj, he feels quite anxious, but after a few drinks, he finds that he can genuinely talk with someone of the other sex.
When Leonard wishes to share a paper they co-authored at a physics convention and Sheldon declines, their friendship is put to the test.
Leonard tells Penny a lie in order to escape with Sheldon from seeing her perform in a stage show, but Sheldon's deception spirals out of control and becomes extremely complicated.
When Sheldon is sick, his friends Leonard, Howard, and Raj vanish without telling anybody, leaving Penny to take care of him despite her discomfort.
Sheldon's confidence is destroyed when he meets Dennis, a 15-year-old physicist who proves to be more intelligent than he is. Leonard offers to help Sheldon in discrediting Dennis's outstanding research.
Sheldon's obsession with proving his supremacy over Leonard, Howard, and Raj leads them to remove him from their college physics team and replace him with Leslie, his bitterest rival.
When Sheldon, Leonard, Howard, and Raj's full-scale model of the time machine makes Penny miss work, she becomes angry with them. Leonard then gives away all of his strange possessions, especially after Penny teases him about it.
When Sheldon's twin sister comes to town, Leonard, Howard, and Raj quarrel and compete for her affections. Raj participates in a medication experiment to treat his selective mutism.
Penny tries to arrange Leonard a surprise party after finding out that he doesn't celebrate birthdays. Sheldon distracts her, though, when he unexpectedly gets to fulfill one of his biggest dreams at an electronics store.
Leonard finds the confidence to ask Penny out on a date when she splits from her boyfriend. Both of them look to Sheldon for advice and to learn what could make or ruin a date.