The rise of antimicrobial resistance (AMR) to the plethora of current antibiotics constitutes a major threat to public health, urging for the discovery of novel antibiotics through natural products. This study explores the potential of ten cinnamaldehyde analogues as novel antibacterial agents against model organisms, namely Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. Antibacterial activity and structure-activity relationships (SARs) were assessed using high-throughput screening (HTS) and minimum inhibitory concentration (MIC) assays, with ampicillin included as a standard control compound. Synergy was evaluated through checkerboard assays with ampicillin and neomycin. Hydroxylated cinnamaldehyde analogues, namely 1.2 and 1.3, exhibited enhanced bioactivity against Escherichia coli when compared to the parent compound (cinnamaldehyde). Most ketone derivatives resulted in minimal or reduced potency with the exception of 2.3 (MIC at 5mM with a 17.26% growth). Compounds 1.1, 1.2, 1.3 aldehydes exhibited an MIC (5 mM, 2.5 mM, 0.016 mM respectively) and adequate microbial growth inhibition (2.33-9.49%) for Staphylococcus aureus. Interestingly, ketones 2.3, 2.4 resulted in MICs at 5 mM with ~ 15% microbial growth. As for Pseudomonas aeruginosa, a similar trend of ketone inactivity was observed with none of them achieving more than 55.8% inhibition. The aldehyde group here presented better efficacy. Specifically, compounds 1.1, 1.2 with MIC = 5 mM and MIC = 2.5 mM respectively. Notably, compound 1.1 was able to achieve complete inhibition at the concentration of 5 mM. The importance of keeping the aldehyde core while strategically adding hydroxyl groups and bromine for antimicrobial efficacy was highlighted through SAR analysis. Synergistic effect trials with ampicillin and neomycin revealed mainly indifferent interactions, with cases of additive and synergistic effects related to potency alone.