Lrrfip1 is an up-regulated protein after cerebral ischaemia whose precise role in the brain both in healthy and ischaemic conditions is unclear. Different Lrrfip1 isoforms with distinct roles have been reported in human and mouse species. The present study aimed to analyse the Lrrfip1 transcriptional variants expressed in rat cortex, to characterise their expression patterns and subcellular location after ischaemia, and to define their putative role in the brain. Five transcripts were identified and three of them (Lrrfip1, CRA_g and CRA_a' (Flap-1)) were analysed by qPCR. All the transcripts were up-regulated and showed differential expression patterns after in-vivo and in-vitro ischaemia models. The main isoform, Lrrfip1, was found to be up-regulated from the acute to the late phases of ischaemia in the cytoplasm of neurons and astrocytes of the peri-infarct area. This study demonstrates that Lrrfip1 activates β-catenin, Akt, and mTOR proteins in astrocytes and positively regulates the expression of the glutamate transporter GLT-1. Our findings point to Lrrfip1 as a key brain protein that regulates pro-survival pathways and proteins and encourages further studies to elucidate its role in cerebral ischaemia as a potential target to prevent brain damage and promote functional recovery after stroke.