Aims: This systematic review was carried out to determine whether synthetic peptidomimetics exhibit significant advantages over antimicrobial peptides (AMPs) in terms of in vitro potency. Structural features – molecular weight, charge and length – were examined for correlations with activity. Methods: Original research articles reporting minimum inhibitory concentration (MIC) values against Escherichia coli, indexed until 31 December 2020, were searched in PubMed/ScienceDirect/Google Scholar and evaluated using mixed-effects models. Results: In vitro antimicrobial activity of peptidomimetics resembled that of AMPs. Net charge significantly affected MIC values (p < 0.001) with a trend of 4.6% decrease for increments in charge by +1. Conclusion: AMPs and antibacterial peptidomimetics exhibit similar potencies, providing an opportunity to exploit the advantageous stability and bioavailability typically associated with peptidomimetics.