The concept of intratumoral microbiota is gaining attention in current research. Tumor-associated microbiota can activate oncogenic signaling pathways such as NF-kappa B, thereby promoting tumor development and progression. Numerous studies have demonstrated that curcumin and its analogs possess strong antitumor effects by targeting the NF-kappa B signaling pathway, along with potent antibacterial properties. In this study, we tested the antibacterial activity of two curcuminoids, Py-cPen and V-cPen, against the Gram-negative bacterial strains Pseudomonas aeruginosa and Escherichia coli and the Gram-positive bacterial strain Streptococcus aureus using in vitro assays and fluorescent microscopy. We observed that both Py-cPen and V-cPen reduced NF-kappa B activation upon lipopolysacharide (LPS) challenge in cell assays. In addition, our findings indicate that Py-cPen and V-cPen interact with LPS, as demonstrated by transmission electron microscopy and confirmed using in silico analyses, thereby modulating LPS activity. Overall, our data indicate that Py-cPen and V-cPen exhibit strong antibacterial and antiinflammatory properties, suggesting their potential as candidates for new multitarget therapeutic strategies.