<jats:title>Significance</jats:title> <jats:p>We demonstrate yeast’s capacity for biosynthesis of complex plant natural products by reconstructing a de novo noscapine biosynthetic pathway and optimizing noscapine production toward scalable manufacturing. Engineered strain contains 25 heterologous plant, bacteria, and mammalian genes and 6 mutant or overexpressed yeast genes. The noscapine biosynthetic pathway incorporates seven endomembrane-localized plant enzymes, highlighting yeast’s ability to functionally express and properly localize large numbers of heterologous enzymes into the endoplasm reticulum. Noscapine titers were improved by 18,000-fold (to low mg/L levels) via a combination of enzyme engineering, pathway and strain engineering, and fermentation optimization. We demonstrated that microbial fermentation can be used to produce halogenated alkaloid derivatives, which can ultimately serve as potential drug leads, through feeding amino acid derivatives to strains.