Conventional antibiotic therapy is often challenged by poor drug penetration/accumulation at infection sites and poses a significant burden to public health. Effective strategies to enhance the therapeutic efficacy of our existing arsenal include the use of nanoparticulate delivery platforms to improve drug targeting and minimize adverse effects. However, these nanocarriers are often challenged by poor loading efficiency, rapid release and inefficient targeting. Nucleic acid hybrid nanocarriers are nucleic acid nanosystems complexed or functionalized with organic or inorganic materials. Despite their immense potential in antimicrobial therapy, they are seldom utilized against pathogenic bacteria. With the emergence of antimicrobial resistance and the associated complex interplay of factors involved in antibiotic resistance, nucleic acid hybrids represent a unique opportunity to deliver antimicrobials against resistant pathogens and to target specific genes that control virulence or resistance. This review provides an unbiased overview on fabricating strategies for nucleic acid hybrids and addresses the challenges of pristine oligonucleotide nanocarriers. We report recent applications to enhance pathogen targeting, binding and control drug release. As multifunctional next-generational antimicrobials, the challenges and prospect of these nanocarriers are included.