Holger A. Klein was educated in Art History, Early Christian Archaeology, and German Literature at the universities of Freiburg im Breisgau, Munich, London, and Bonn. His research focuses on Late Antique, Early Medieval, and Byzantine art and architecture, more specifically, on the cult of relics, reliquaries, and issues of cultural and artistic exchange.

Professor Klein joined Columbia University as an Assistant Professor in 2000, was promoted to tenured Associate Professor in 2006, and to Professor in 2011. In 2015–16, he held an Alliance Visiting Professorship at the Université Paris I Panthéon-Sorbonne and taught Columbia undergraduates at Reid Hall. He was named The Lisa and Bernard Selz Professor of Medieval Art History in 2018.

At Columbia University, Professor Klein has served as Director of Art Humanities (2003; 2007–09), Director of Graduate Studies (2010–12; 2017–20), and as Department Chair (2012–15). He currently serves as Director of the Sakıp Sabancı Center for Turkish Studies and Faculty Director of Casa Muraro in Venice.

From 2004–07 he held an appointment as the Robert P. Bergman Curator of Medieval Art at the Cleveland Museum of Art and continued to oversee the reinstallation of the museum's renowned collection of Medieval and Byzantine art until 2010. His work as a curator includes various international loan exhibitions, among them Restoring Byzantium, The Kariye Camii in Istanbul and the Byzantine Institute Restoration (Wallach Art Gallery, 2004), Medieval Treasures from The Cleveland Museum of Art (Bayerisches Nationalmuseum/The J. Paul Getty Museum, 2007–08), Treasures of Heaven, and Saints, Relics and Devotion in Medieval Europe (Cleveland Museum of Art/Walters Art Museum/British Museum, 2010–11).

Professor Klein is the recipient of several awards and prizes, including the 50th annual Mark Van Doren Award for Teaching (2011), which honors a Columbia professor's commitment to undergraduate instruction as well as inspiring leadership; the Lenfest Distinguished Faculty Award (2012), which recognizes unusual merit as a teacher of undergraduate and graduate students as well as outstanding scholarship; and the Wm. Theodore de Bary Award for Distinguished Service to the Core Curriculum (2014). He was named a Distinguished Research Fellow of Sabancı University in 2020.