Miller joined the IU faculty in 1957. The majority of his work revolved around cytokinin-related substances. In the early 1960s, Miller extracted zeatin from maize endosperm, showing the first instance of a naturally occurring adenine-based cytokinin. He retired from teaching in 1987, but continued his research up until his death in 2012. His last project focused on an herb, Lindenbergia muraria. Miller had discovered a compound that promoted flowering and was investigating how environmental factors interact with that compound.

In 1999, Carlos established the Carlos O. Miller Chair of Plant Growth and Development to help strengthen IU's efforts to build a group with research emphasis on the biochemistry of plant growth and development. Miller felt the field would assume an increasing importance in agriculture as the world human population increased. He endowed and established the Carlos O. Miller Graduate Fellowship in Plant Developmental Biology in 2007.