Miller graduated from Rahway High School in before attending Brown University. At Brown, he received his Sc.B. in biology in 1970. He earned his Ph.D. in biology from the University of Colorado at Boulder in 1974. From 1974 to 1980, he taught at Harvard University. His research involves problems of structure and function in biological membranes, often involving electron microscopy.

Miller has proudly voiced his support for what he calls "pro-science" candidates in politics. He has actively campaigned for school board and education candidates who support the teaching of evolution in Kansas and Ohio. In the science community, he has sought to elevate the understanding of scientists of the roots of the creationist movement, and to encourage the popularization of scientific concepts.

Miller has appeared in court as a witness, and on panels debating the teaching of intelligent design in schools. In 2002, the Ohio State Board of Education held a public debate between two scientists, including Miller, and two proponents of intelligent design. He testified for the plaintiffs, but only as a fact witness (not as an expert), in Selman v. Cobb County, testing the legality of stickers calling evolution a "theory, not a fact" that were placed on the biology textbook Miller authored. In 2005, the judge ruled that the stickers violated the Establishment Clause of the First Amendment to the United States Constitution. This decision was vacated on appeal because of missing records of the previous trial. The case was remanded for additional evidentiary inquiry and new findings, and a list of factual issues that the court would probably want to address included as item 15 a reference to Miller's testimony regarding “the colloquial or popular understanding of the term [theory]” and the suggested question as to whether he has any qualifications to testify as an expert on the popular meaning of the word "theory". The case was remanded back to the lower court and was eventually settled out of court. Miller was also the plaintiff's lead expert witness in the Kitzmiller v. Dover Area School District, challenging the school board's mandate to incorporate intelligent design into the curriculum. The judge in that case also ruled decisively in favor of the plaintiffs.

In 2006 the American Society for Cell Biology gave him a Public Service Award. The American Association for the Advancement of Science (AAAS) also recognized Miller for his contribution to the public education of evolution in the United States. Miller also appeared at the 2006 Dwight H. Terry Lectureship at Yale University, delivering his lecture "Darwin, God, and Dover: What the Collapse of 'Intelligent Design' Means for Science and for Faith in America." He won the 2008 AAAS Award for Public Understanding of Science and Technology.

Miller is known for his appearances on the Comedy Central television show The Colbert Report. Dr. Miller has also made many appearances on C-SPAN debating proponents of creationism and intelligent design. He has debated several supporters of intelligent design including biochemist Michael J. Behe.

He gave a Faraday Institute lecture in April 2009 on "God, Darwin and Design" and appeared on the Today Programme arguing, "The issue of God is an issue on which reasonable people may differ, but I certainly think that it's an over-statement of our scientific knowledge and understanding to argue that science in general, or evolutionary biology in particular, proves in any way that there is no God."

He also speaks at conferences, notably the Skeptics Society's Origins Conference in October 2008 with Nancey Murphy, Hugh Ross, Leonard Susskind, Sean Carroll, Paul Davies, Christof Koch, Donald Prothero, and Victor J. Stenger.