[16][17] In 1990, he left the UK to begin his doctoral studies under the direction of Professor Larry Overman at the University of California, Irvine.

MacMillan's graduate studies culminated in the total synthesis of 7-(−)-deacetoxyalcyonin acetate, a eunicellin diterpenoid isolated from the soft coral Eunicella stricta.

[17] MacMillan began his independent research career as a member of the chemistry faculty at the University of California, Berkeley in July 1998.

[19][20] He developed catalysts that can drive asymmetric catalysis, in which a reaction produces more of the left-handed version of a molecule than the right-handed one (chirality), or vice versa.

[19] MacMillan's research group has made many advances in the field of asymmetric organocatalysis, and they have applied these new methods to the synthesis of a range of complex natural products.

In September 2024, he will attend the Brazilian Meeting on Organic Synthesis in Bento Gonçalves, Rio Grande do Sul, as opening lecture.