Miller has been developing algorithms and software for analyzing DNA sequences and related types of data from molecular genetics.

[6][7] He also develops methods for aligning long DNA sequences and extracting functional information from them.

Webb Miller's recent research interests[8][9] include the bioinformatics of species extinction, collaborating with Stephan Schuster, who is a Professor of Biochemistry and Molecular Biology at Penn State.

In November 2008, they published a paper in Nature that described a draft sequence for the woolly mammoth genome.

Together with Gene Myers, he received the Inaugural IEEE Frances E. Allen Medal[11] "for pioneering contributions to sequence analysis algorithms and their applications to biosequence search, genome sequencing, and comparative genome analyses".