Curcumin, a yellow pigment in Asian spice, is a natural polyphenol component of Curcuma longa rhizome. Curcuminoid components include curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC). Previous studies established curcumin as a safe agent based on preclinical and clinical evaluations and curcuminoids have been approved by the US Food and Drug Administration (FDA) as “Generally Recognized as Safe” (GRAS). The present review collects and summarizes clinical and preclinical studies of curcumin interactions, with an emphasis on the effect of curcumin and curcumin analogs on the mRNA and protein levels of microsomal CYP450 enzymes (phase I metabolism) and their interactions with toxicants, drugs and drug probes. The literature search was conducted using keywords in various scientific databases, including Web of Science, Scopus, PubMed, and Google Scholar. Studies concerning the impact of curcumin and curcumin analogs on microsomal enzyme activity are reviewed and include oral, topical, and systemic treatment in humans and experimental animals, as well as studies from in vitro research. When taken together, the data identified some inconsistent results between various studies. The findings showed significant inhibition of CYP450 enzymes by curcumin and its analogs. However, such effects are often differed when curcumin and curcumin analogs were coadministered with toxicant and other drugs and drug probes. We conclude from this review that herb-drug interactions should be considered when curcumin and curcumin analogs are consumed.