The most abundant cells in the tumor microenvironment are cancer-associated fibroblasts (CAFs). They play an important role in oral squamous cell carcinoma (OSCC) angiogenesis, invasion and metastasis. Platelet-derived growth factor (PDGF)-BB has an obvious regulating effect on the formation of CAFs through binding to PDGF receptor (PDGFR)-β, but the role of long non-coding (lnc)RNA in PDGF-BB-induced transformation of fibroblasts into CAFs remains poorly understood. Using an lncRNA ChIP, 370 lncRNA transcripts were identified to be significantly and differentially expressed between fibroblasts and PDGF-BB-induced fibroblasts, including 240 upregulated lncRNAs and 130 downregulated lncRNAs, indicating that lncRNAs are involved in the regulation of the transformation of CAFs. Previous studies have shown that the nuclear factor (NF)-κB signaling pathway plays an important role in the activation of CAFs. Dual-luciferase reporter assay and co-immunoprecipitation were conducted to confirm that the leucine-rich adaptor protein 1-like (LURAP1L), which is the target of lncRNA LURAP1L antisense RNA 1 (LURAP1L-AS1) had a positive regulatory effect on I-κB kinase (IKK)/NF-κB signaling. Therefore, LURAP1L-AS1 was selected and PDGF-BB was demonstrated to upregulate the expression of LURAP1L-AS1 and LURAP1L, which was reversed by a PDGFR-β inhibitor. Subsequently, knocking down LURAP1L-AS1 suppressed the expression of PDGF-BB-induced fibroblast activation marker protein α-smooth muscle actin, fibroblast activation protein-α, PDGFR-β and phosphorylated (p)-PDGFR-β. IKKα, p-IĸB and p-NF-κB were downregulated by the knockdown of LURAP1L-AS1 and upregulated by overexpression of LURAP1L-AS1. The present study indicates that LURAP1L-AS1/LURAP1L/IKK/IĸB/NF-κB plays an important regulatory role in PDGF-BB-induced fibroblast activation and may become a potential target for the treatment of OSCC.