The series stars Clark Gregg as Phil Coulson, reprising his role from the film series, alongside Ming-Na Wen, Brett Dalton, Chloe Bennet, Iain De Caestecker, and Elizabeth Henstridge. Nick Blood, Adrianne Palicki, Henry Simmons, Luke Mitchell, John Hannah, Natalia Cordova-Buckley, and Jeff Ward joined in later seasons. The S.H.I.E.L.D. agents deal with various unusual cases and enemies, including Hydra, Inhumans, Life Model Decoys, alien species such as the Kree and Chronicoms, and time travel. Several episodes directly crossover with MCU films or other television series, notably Captain America: The Winter Soldier (2014) which significantly affected the series in its first season. In addition to Gregg, other actors from throughout the MCU also appear in guest roles.

Joss Whedon, writer and director of the MCU film The Avengers (2012), began developing a S.H.I.E.L.D. pilot in August 2012. Gregg was confirmed to reprise his role that October, and the series was officially picked up by ABC in May 2013. The series attempted to replicate the production value of the MCU films on a broadcast television budget, while also having to work within the constraints of the MCU which were dictated by Marvel Studios and the films. Prosthetic makeup was created by Glenn Hetrick's Optic Nerve Studios, while Legacy Effects contributed other practical effects. Composer Bear McCreary recorded each episode's score with a full orchestra, and the visual effects for the series were created by several different vendors and have been nominated for multiple awards.

The series premiered on ABC in the United States on September 24, 2013, and concluded with a two-part series finale on August 12, 2020, with 136 episodes broadcast over seven seasons. After starting the first season with high ratings but mixed reviews, the ratings began to drop while reviews improved. Ratings continued to lower with subsequent seasons, but were more consistent within each season, while reviews for later seasons were consistently positive. Several characters created for the series have since been introduced to the comic universe and other media. An online digital series, Agents of S.H.I.E.L.D.: Slingshot, centered on Cordova-Buckley's Elena "Yo-Yo" Rodriguez, was released in December 2016 on ABC.com.