AMPK is a ubiquitous cellular energy sensor enzyme that upon activation by cellular stresses mediates the downregulation of adenosine triphosphate (ATP) consuming molecular pathways. This action ultimately protects the cell from ATP depletion, apoptosis, and cellular death. We find here that the active kinase of AMPK, which resides in the PRKAA1 subunit isoform 1, is controlled by the action of a promoter-associated antisense long non-coding RNA (asLncRNA). We describe two small siRNAs, si-P1 and si-P4, that target lncRNAs associated with the AMPK promoter and can control the ratio of active isoform 1 to inactive isoform 5. si-P4 significantly repressed promoter-associated transcripts. Moreover, we show that this control of PRKAA1 isoform inclusion can be controlled by shRNA-delivered extracellular vesicles, suggesting a means of imparting superlative control of cellular metabolism using EV-delivered asLncRNA-targeted RNAs. To this end, we developed two plasmid constructs that express either si-P1 or si-P4, Argonaute 2 (AGO2) for RNA silencing, and Cx43 to facilitate exosome release. HEK293T cells transfected with these constructs cultured in a transwell assay were able to perturb the ratio between isoform 1 and isoform 5, indicating the possible use of EVs as a therapy for diseases involving AMPK.