Neutrophils represent one of the most abundant leukocytes in circulation and play a crucial role in the immune response during bacterial infection. Group A Streptococcus (Strep A), is a human-specific pathogen that can cause self-limiting infections, including pharyngitis and impetigo, as well as invasive pathologies such as necrotising fasciitis and streptococcal toxic shock syndrome. Previous research has demonstrated that hypervirulent strains of Strep A can alter neutrophil cellular pathways, including cell death and pro-inflammatory responses, however the neutrophil response to Strep A remains poorly characterised. Herein, we employed a sequential, dual-omics approach to characterise the human neutrophil response to the globally disseminated emm1 lineage of Strep A. Transcriptomics via bulk RNA sequencing following a two-hour in vitro infection suggests that microRNA regulation, phosphorylation, and lipid metabolism are modulated in neutrophils in response to Strep A. These data point to potential intracellular mechanisms that may contribute to the pro-inflammatory neutrophil response seen during infection with hypervirulent Strep A. These findings also reveal a dynamic transcriptomic profile for neutrophils infected with Strep A more generally, providing insight into overall neutrophil response during bacterial infection. The second arm of our dual-omics investigation explored neutrophil lipidomic shifts during Strep A infections using a single-cell mass spectrometry imaging (MSI) protocol. Following initial optimisation of the imaging protocol, pilot experiments showed unique lipid shifts in neutrophils following Strep A infection. This work provides further insights into the complex nature of interactions between neutrophils and Strep A and identifies a need to characterise underexplored pathways within neutrophils in the context of infection.