The innate immune response to LPS is highly dynamic yet tightly regulated. Gene expression is controlled at multiple steps including transcription, mRNA export, RNA stability and rate of translation. While our understanding of the processes involved in gene expression has been rapidly expanding we have a lesser understanding of how post-transcriptional pathways are regulated in response to inflammatory stimuli. The rate of RNA degradation of specific transcripts in comparison to its new transcription is important for overall expression. This has been well-established for a handful of cytokines including tumour necrosis factor alpha. Multiple RNA stability pathways act co-ordinately to control mRNA transcripts levels. These pathways include nonsense mediated decay, the RNA decay exosome, P-body localised deadenylation, decapping and degradation and AU-rich element targeted decay mediated by tristetraprolin. We treated bone marrow derived macrophages with LPS over a time course in the presence and absence of the transcription inhibitor alpha-amanatin and analysed the transcriptional profiles by RNA sequencing. Our data shows that components of RNA degradation pathways are regulated during an LPS response. Components of the exosome are down-regulated including the core catalytic component, Dis3, indicating that exosomal degradation of transcripts during an LPS response is limited. In contrast the P body associated decapping enzymes DCP1A and DCP2, 5’exonuclease XRN1 and components of the cytoplasmic deadenylation complex are induced suggesting increased degradation by this pathway. Regulation of these transcripts occurred at both a transcriptional and post-transcriptional level. Further key proteins in the nonsense mediated decay pathway were induced at the mRNA level at later timepoints and phosphorylation of Upf1 by the central kinase of NMD, SMG1, was increased at early timepoints.  These finding suggest that LPS activation of macrophages results in targeted regulation of RNA degradation pathways in order to change how subsets of mRNAs are degraded during an inflammatory response.