This study aimed to evaluate the inhibitory effects of phenolic‐rich extracts from acerola (Malpighia emarginata D.C., PEA), cashew apple (Anacardium occidentale L., PEC) and mango (Mangifera indica L., PEM) by‐products on distinct enterotoxigenic Escherichia coli (ETEC) strains. The capability of PEA and PEC of impairing various physiological functions of ETEC strains was investigated with multiparametric flow cytometry. Procyanidin B2, myricetin and p‐coumaric acid were the major phenolic compounds in PEA, PEC and PEM, respectively. PEA and PEC had lower minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) (MIC: 31·25 mg ml−1; MBC: 62·5 mg ml−1) on ETEC strains than PEM (MIC and MIC: >1000 mg ml−1). PEA and PEC (15·6, 31·2, 62·5 mg ml−1) caused viable count reductions (P < 0·05) on ETEC strains after 24 h of exposure, notably the ≥3 log reductions caused by 62·5 mg ml−1. The 24 h exposure of ETEC strains to PEA and PEC (31·2, 62·5 mg ml−1) led to high sizes of cell subpopulations with concomitant impairments in cell membrane polarization and permeability, as well as in enzymatic, respiratory and efflux activities. PEA and PEC are effective in inhibiting ETEC through a multi‐target action mode with disturbance in different physiological functions. Significance and Impact of the Study: Enterotoxigenic Escherichia coli (ETEC) is one of the main causes of diarrhoea in humans and animals. The increasing resistance of ETEC strains to clinically relevant antibiotics has prompt the necessity to search for novel substances with inhibitory efficacy. This is the first study showing the capability of phenolic‐rich extracts of acerola and cashew apple by‐products causing the inhibition of distinct ETEC strains, with disturbance of various physiological functions, indicating these substances as potential antimicrobials to be exploited in solutions to control ETEC in humans and animals.