Аннотация:Summary Californian populations of Echinochloa phyllopogon have evolved multiple‐herbicide resistance ( MHR ), posing a threat to rice production in California. Previously, we identified two CYP 81A cytochrome P450 genes whose overexpression is associated with resistance to acetolactate synthase ( ALS ) inhibitors from two chemical groups. Resistance mechanisms to other herbicides remain unknown. We analyzed the sensitivity of an MHR line to acetyl‐CoA carboxylase ( ACC ase) inhibitors from three chemical groups, followed by an analysis of herbicide metabolism and segregation of resistance of the progenies in sensitive (S) and MHR lines. ACC ase herbicide metabolizing function was investigated in the two previously identified P450s. MHR plants exhibited resistance to all the ACC ase inhibitors by enhanced herbicide metabolism. Resistance to the ACC ase inhibitors segregated in a 3 : 1 ratio in the F 2 generation and completely co‐segregated with ALS inhibitor resistance in F 6 lines. Expression of the respective P450 genes conferred resistance to the three herbicides in rice, which is in line with the detection of hydroxylated herbicide metabolites in vivo in transformed yeast. CYP 81As are super P450s that metabolize multiple herbicides from five chemical classes, and concurrent overexpression of the P450s induces metabolism‐based resistance to the three ACC ase inhibitors in MHR E. phyllopogon , as it does to ALS inhibitors.