The series follows the life of Meredith Grey (Ellen Pompeo), the daughter of the famous general surgeon Ellis Grey (Kate Burton), starting from her acceptance into the surgical residency program at the fictional Seattle Grace Hospital (later named Seattle Grace Mercy West and finally, Grey Sloan Memorial Hospital). During her time as an intern, Grey works alongside fellow physicians Cristina Yang (Sandra Oh), Izzie Stevens (Katherine Heigl), Alex Karev (Justin Chambers) and George O'Malley (T. R. Knight), who each struggle to balance their personal lives with hectic schedules and stressful residency requirements. During their internship, they are overseen by Miranda Bailey (Chandra Wilson), a senior resident, who works with attending physicians Derek Shepherd (Patrick Dempsey), head of neurosurgery and Meredith's love interest, and Preston Burke (Isaiah Washington), head of cardiothoracic surgery, who becomes Yang's fiancé. Richard Webber (James Pickens Jr.), Chief of Surgery and attending general surgeon, is the former lover of Ellis Grey. During the first 6 seasons, Burke, O'Malley, and Stevens all depart the series.

The series also shows drama and emotions focused on Meredith's life. In addition to Webber, Burke, and Shepherd, the surgical wing is primarily supervised by Addison Montgomery (Kate Walsh), Shepherd's ex-wife and the head of OB/GYN, neonatal and fetal surgery who leaves for Los Angeles at the end of season 3; Mark Sloan (Eric Dane), head of plastic surgery; Callie Torres (Sara Ramirez), a resident who later becomes head of orthopedic surgery and leaves Seattle for New York at the end of the 12th season; Erica Hahn (Brooke Smith), as head of cardiothoracic surgery, who leaves Seattle Grace in season 5 after a disagreement with Torres, with whom she shared a brief relationship; Owen Hunt (Kevin McKidd), as head of trauma who later marries and divorces Yang; Arizona Robbins (Jessica Capshaw), as head of pediatric surgery, and later head of maternal / fetal surgery who marries Torres; Teddy Altman (Kim Raver), as head of cardiothoracic surgery who departs at the end of season 8 but returns in season 14; and Amelia Shepherd (Caterina Scorsone), Derek's sister, who is hired to replace him as head of neurosurgery.

Lexie Grey (Chyler Leigh), Meredith's paternal half-sister, joins the residency program in season 4 until her death with her love-interest Mark Sloan in the plane crash at the end of season 8, after which Seattle Grace is renamed Grey Sloan Memorial Hospital in their memory. Former Mercy-West residents April Kepner (Sarah Drew) and Jackson Avery (Jesse Williams) join Seattle Grace following an administrative merger in season 6. Other additions include Leah Murphy (Tessa Ferrer), who departs at the end of season 10 but returns during season 13; Shane Ross (Gaius Charles), who leaves with Yang for Zurich, Switzerland, in the season 10 finale; Stephanie Edwards (Jerrika Hinton), who resigns at the end of season 13; Jo Wilson (Camilla Luddington), who marries Karev; Andrew DeLuca (Giacomo Gianniotti), the former love interest of Meredith's maternal half sister Maggie Pierce (Kelly McCreary) who also serves as head of cardiothoracic surgery; and Ben Warren (Jason George), an anesthesiologist turned resident turned firefighter[8] who marries Bailey. Season 11 sees the death of Derek Shepherd, and in season 12, attending cardiovascular surgeon Nathan Riggs (Martin Henderson) joins the show. In the early episodes of season 1