Merz joined the chemistry department at the Pennsylvania State University as an assistant professor in 1989. He was promoted to an associate professor in 1996 and professor in 1998. While at the Pennsylvania State University he took a sabbatical to work in the biopharmaceutical industry (1998-2001) as the senior director of the Center for Informatics and Drug Discovery (CIDD) at Pharmacopeia, Inc. and as the senior director of the ADMET Research and Development Group in the Accelrys software division of Pharmacopeia. He also founded, in 2001, the software company QuantumBio, Inc located in State College, Pennsylvania. In 2005, he joined the faculty at the University of Florida in the chemistry department and as part of the Quantum Theory Project. While he was at University of Florida, he was named the Colonel Allan R. and Margaret G. Crow Term Professor, 2009-2011, the University of Florida Research Foundation (UFRF) Professor, 2011-2013 and the Edmund H. Prominski Professor of Chemistry, 2011-2013. In 2013, Merz moved to Michigan State University as a professor in the Chemistry and Biochemistry and Molecular Biology Departments. He was the director of the Institute of Cyber-enabled Research (2013-2019) and is the Joseph Zichis Chair in Chemistry and a university distinguished professor. While his primary appointment is at Michigan State University, he has also held visiting Professorships at Imperial College, the Institute for Research in Biomedicine, École Polytechnique, University of Florence, University of Strasbourg, University of Oviedo and ETH Zurich.