Heat stress (HS) seriously affects sow lactation performance and Long non-coding RNAs (lncRNAs) play vital roles in the regulation of transcription and post transcription. However, the mechanism of lncRNAs expression affecting lactation performance on the hypothalamus-pituitary-mammary axis of sows is still unclear. In this study, we performed RNA sequencing and bioinformatics analysis of the hypothalamus, pituitary, and mammary gland tissues of lactating sows under HS and thermal comfort. In total, the analysis identified 658, 6021, and 6745 differently expressed (DE) mRNAs, 26, 126, and 169 DE lncRNAs between comparison groups in the hypothalamus, pituitary, and mammary glands, respectively. The hormone genes and most DE mRNAs encoding heat shock protein were differently expressed in the HS group. In addition, 2, 60, and 86 pairs of DE lncRNAs and mRNAs correlation were observed in those tissues, respectively. Some lncRNAs may be involved in the regulation of lactation performance in the HS sows. Copyright © 2020 Elsevier Inc. All rights reserved.