Recent medical school graduate Emily Owens is now a first-year surgical intern at Denver Memorial Hospital and she is ready to leave high school persona of geeky-girl-with-flop-sweats behind her. But Emily quickly realizes that a hospital is a lot like high school -- cliques and all -- when she is faced with her medical school crush Will Collins and high school nemesis Cassandra Kopelson. On top of that, Emily manages to get herself in some hot water with her attending Dr. Gina Bandari, as well as the nurses, on her first day. Another fellow intern, Tyra Dupre latches onto Emily as a new friend, and immediately begins confiding all her personal information, including the fact that Tyra is a lesbian, and that she hasn’t come out to her father, who happens to be the Chief of Surgery, Dr. Dupre (Harry Lennix). Emily is also getting to know the slightly nerdy, but smart and handsome resident Dr. Micah Barnes, who is facing some serious medical issues within his own family.
Emily is unaware of her bad reputation with the nurses until one of them gives her a very specific case as revenge. After Emily reveals her feelings to Will, she tries to avoid anymore awkwardness by telling him she already has another crush. With a patient’s life hanging in the balance, Emily contemplates using the secret she knows about the chief to get a speedy approval on a procedure. Meanwhile, Micah is surprised to find someone new entertaining his mother during her chemotherapy.
When the surgical interns are given an impromptu medical quiz with a chance to assist in surgery as the prize, only Emily and Cassandra are left standing. After an STD outbreak at a local high school becomes an issue, Emily reluctantly agrees to speak to a group of high school girls about safe sex. Meanwhile, Emily continues to try to forget about her feelings for Will, but finds the task easier said than done.
Emily and Micah are frantic when they discover their patient needs a kidney transplant immediately, but they are baffled when she mysteriously refuses to accept the kidney from her new husband. Elsewhere, Emily assists Dr. Hamada (Brittany Ishibashi) and Dr. Bandari, with a risky surgery after they discover that one of the babies their patient is carrying for her sister suffers from a defective heart valve. Meanwhile, in an effort to keep Cassandra away from Will, Emily tries to land the job as Dr. Bandari’s research assistant. However, her competition is Cassandra, who is willing to play dirty in order to get what she wants.
Emily suffers a major embarrassment in front of her colleagues at the hands of a drug-impaired patient. In the aftermath, Emily decides to follow Dr. Bandari's advice and tries to toughen up. Emily and Will find that a teenage patient needs a partial liver transplant, but they uncover some surprising information when neither of the teen's parents is a match. Meanwhile, Cassandra starts treating Emily better in an effort to learn more about Will, and Tyra sets Emily up on a date with her ex, a fact which she doesn't reveal to Emily.
When a female car accident victim is brought into the ER with a spike through her torso, everyone immediately blames her boyfriend for causing the accident. She makes it through surgery, but the doctors find that she may be paralysed. Later, they discover that the boyfriend has lupus, which could be to blame for the accident. The case brings up painful memories for Will. Emily deals with a model with jaw cancer who refuses to undergo surgery. Emily and Cassandra compete for Will's attention as they all prepare for the in-service exam.
A man gets admitted in a costume and claims to be King Paravel from the Elvish nation. The man later goes blind which leads Will to believe he is suffering from conversion disorder, a psychiatric problem. Emily refuses to jump to conclusion so quickly. Another patient is a woman diagnosed with cancer who later passes away due to an unexpected cardiac arrest. Her upset daughter sues Micah for medical malpractice. In an attempt to prove that she is not predictable, Emily agrees to let Tyra dress her up for a blind date arranged by Cassandra. Emily shows up to the date beautifully which later causes Will to act jealous. Micah realizes his true feelings for Kelly. Doctor Bendari realizes she has been putting career before life and attempts to change it.
After a year long absence, Dr. A.J. Aquino returns to Denver Memorial, but before he can rejoin the staff, the Chief insists that he make peace with Dr. Bandari. Emily is tasked with treating a patient who claims to be a psychic, and is convinced that her tarot cards predict her own impending death. Elsewhere, Cassandra and Dr. Bandari treat a patient who needs a lung transplant, but Micah’s discovery of a new medical issue leaves the patient with a tough decision. Meanwhile, Emily decides to test her theory that Will was jealous of her recent date, so Tyra offers to teach Emily how to flirt.
When Emily, Will and Cassandra compete against each other to be Dr. Bandari's research assistant, feelings get hurt when they have to describe each other's flaws. Emily is determined to solve the medical mystery of a young patient whose x-rays reveals a bullet lodged in his lung, but who has no signs of a gunshot wound or scar. Meanwhile, Emily comes to a revelation about her personal life after diagnosing a daredevil with a rare disease that forces him to change his entire life.
When the hospital is inundated with bus crash victims during a winter storm, Emily is assigned to run triage in the E.R. During the chaos, Emily is forced to do an emergency skull procedure on a heroic Marine who suddenly collapses. Tyra bristles at her father’s lack of respect for her as a doctor, but they later experiences a breakthrough when they perform an emergency c-section together. Meanwhile, Will and Emily secretly work to help an unexpected patient leaving Cassandra to question Will’s true feelings for Emily. Micah finally makes a bold decision in his personal life.
Season Finale: Emily's decision about starting a relationship with Micah becomes even more complicated when Will hears about it and begins to feel jealous. Emily and Tyra treat an unruly woman, but after learning of her home hoarding situation, Emily wonders if the woman's personality changes may be caused by her many cats. Now that Cassandra and Will have broken up, Cassandra's strictly professional behavior distracts Will and causes him to misdiagnose their patient. Meanwhile, Micah's sister comes to town after finding out the truth about their mother.