The occurrence of metritis during the postpartum period causes serious economic losses in dairy cattle. The Micronised Purified Flavonoid Fraction (MPFF) is a polyphenolic flavonoid compound which is considered to have many health-related properties such as antibiotic, anti-inflammatory, phlebotonic, and several vascular-protecting activities. The aim was to evaluate the effects of a new strategic therapy for metritis based on MPFF intrauterine infusions during the early postpartum in dairy cows naturally infected by Escherichia coli. The clinical effects on reproductive anatomical structures and chronological involution dynamics were monitored until day 24 postpartum by ultrasonography. Moreover, uterine bacteriological and cytological (polymorphonuclear neutrophils; PMNs) profiles were analysed before and after MPFF infusion. The results showed that the success rate (% cure) at day 24 postpartum was improved significantly when using higher MPFF doses (p < 0.05). Moreover, MPFF treatment acutely diminished the size of the cervix and uterus and improved the involution process during the first 24 days (p < 0.05). The prevalence of pathogenic bacteria found in in vitro cultures was significantly variable (p < 0.01), as were the antibiotic sensitivity patterns. Pathogenic bacteria isolates decreased after MPFF applications in a dose–response fashion (p < 0.01), while isolates obtained from controls and low-dose-MPFF-treated animals were stable and similar (p > 0.05). The sensitivity patterns of pathogenic bacteria isolated in in vitro cultures from MPFF-treated animals were variable, although resistance to E. coli, Staphylococcus aureus, Bacillus spp., and coliforms was shown irrespective of the MPFF doses used. However, MPFF-treated cows showed a dose–response effect regarding PMN rates (p < 0.05). The calving-first service, calving–conception interval, and conception rate improved significantly from using higher MPFF doses (p < 0.05). In conclusion, this study shows that MPFF treatment differentially affects uterine involution, bacteriological profiles, cytological traits, and reproductive performance in metritis-positive dairy cows naturally infected by E. coli.