Peter Capaldi as Saleem "Sal" Copper
Originally from Wales, he was a child prodigy with an eidetic memory who began college at the age of 11 (after completing the fifth grade), started graduate studies at 14, and earned a PhD at 16. A theoretical physicist researching quantum mechanics and string theory, he has two master's degrees, a PhD and a Sc.D. However, despite his IQ of 187, he finds many routine aspects of social situations and life in general difficult to understand and deal with. He has a poor grasp of other people's feelings and little or no understanding of nuances, often questioning others if a comment is intended as sarcasm. As a result, he is extremely tactless and acts wildly inappropriately much of the time. He is determined have his own way, boasts of his superior intelligence and belittles the accomplishments of his friends, making him appear petty and childlike. Sal has an extremely ritualized way of living (e.g. sitting in the same spot on the sofa in the apartment or knocking on a door three times, each time saying the name of the person he's addressing) and a compulsion to complete things. He is also wary of germs and dislikes physical contact.
Martin Freeman as Leo Hoffman
An experimental physicist with an IQ of 173, he received his PhD when he was 24 years old. His mother, Dr. Bethany Hoffman, is a neuroscientist and psychiatrist who provided little, if any, nurturing when Leonard was growing up. Like all of the other major male characters, he is a nerd who loves video games, comic books and World of Warcraft. The straight man of the series, he shares an apartment in London with colleague and friend Sal Copper.
Bonnie Wright as Jennifer "Jenny"
An aspiring actress from a small town outside of Canterbury, Jenny lives across the hall from Sal and Leo. She has gone to casting calls and auditions, but has not been very successful thus far. To pay the bills, she is a waitress and occasional bartender at The Cheesecake Factory. She attended, but did not graduate from a community college, but has far more common sense and social awareness than the other main characters. She is a bit slovenly and untidy.
Randall Park as Henry "Harry" Mason
He works as an aerospace engineer, is Jewish and lives with his mother. Unlike Sal, Leo, and Raj, Harry lacks a PhD, earning him Sal's scorn. He defends this by pointing out that he has a master's degree in engineering from the elite MIT and that the apparatus he designs are launched into space, unlike the purely abstract work of his friends. He has a marked sense of humor, which Leo and Raj occasionally appreciate. He fancies himself a ladies' man and devises outrageous pick-up lines, which have limited success with women.
Sharlto Copley as Raajih "Raj" Chukwumereije
From Cape Town, South Africa, he works as a particle astrophysicist at Kingston. His family is very wealthy. He talks to his parents, Dr. and Mrs. V.M. Chukwumerije, via webcam. He is very shy around women and is unable to talk to them(except for his mother and his sister), unless he drinks alcohol (or at least thinks he has drunk it) or takes an experimental medication. Unfortunately, the former gives him an outrageous, unpredictable personality, while the latter causes unforeseen side effects. Even so, he often has better luck with women than his overly-confident best friend, Howard. He has very feminine tastes and often takes on a stereotypical female role in his close friendship with Howard, but he insists that he is not gay.
Hayley Atwell as Bette Rocque
A young woman who is initially a waitress co-worker of Jenny's, paying her way through graduate school, studying microbiology. Bette is introduced to Harry by Jenny as a result of an agreement between Harry and Leo that if either ever ended up with a hot girlfriend, he would get the girlfriend to introduce the other to "a hot chick". At first, they do not get along, apparently having nothing in common, until they find out that they both have overbearing mothers.
Natalie Dormer as Alys Floyd
A woman selected by an online dating site as Sal's perfect mate after Raj and Harry secretly set up an account using Sal's information, prompting Raj to comment, "We finally have proof that aliens walk among us!" The two have many similar traits, though Amy eventually becomes more interested in social and romantic interaction and is more socially aware than Sal. Once she and Sal meet, she becomes, as Sal puts it, a girl who is his friend, but not his "girlfriend". Their relationship slowly progresses through seasons 5 and 6 up to the point where Sal considers her his girlfriend. Alys also believes she and Jenny are best friends ("besties", as she puts it), a sentiment that Jenny does not share. Jenny eventually becomes a real friend, overlooking Alys's Sal-like qualities. Alys's admiration for Jenny has at times bordered on physical attraction. Alys has a PhD in neurobiology.
Sam Huntington as Sam Baxter
A brilliant artist, Sam is a graduate of the prestigious Rhode Island School of Design and though he is socially-awkward, he possesses slightly better social skills than the rest of the guys. Unlike the others he is not a techno-geek. During Sam's first appearance, the guys bring Jenny along to the store, and he manages to ask her on a date. They go out a few times, until Jenny mistakenly calls him "Leo" while they are making out, leaving him devastated.