BackgroundTendon injuries are among the most common musculoskeletal disorders. Celecoxib possesses an effective anti-inflammatory activity in the tendon injury treatment. Lactoferrin has a great potential for the tendon regeneration. However, the efficacy of celecoxib combined with lactoferrin in the treatment of tendon injury has not been reported. In this study, we aimed to investigate the effect of celecoxib and lactoferrin on tendon injury and repair, and screen for the crucial genes associated with the tendon injury and repair.MethodsThe rat tendon injury models were established and divided into four groups: normal control group (n= 10), tendon injury model group (n= 10), celecoxib treatment group (n= 10), and celecoxib + lactoferrin treatment group (n= 10). Then, RNA sequencing was performed to identify differentially expressed lncRNAs (DElncRNAs), miRNAs (DEmiRNAs) and mRNAs (DEmRNAs) in celecoxib treatment group and celecoxib + lactoferrin treatment group. Next, autophagy/hypoxia/ferroptosis/pyroptosis-related DEmRNAs were further identified. Subsequently, functional enrichment, protein–protein interaction (PPI) network and transcriptional regulatory network construction for these genes were performed.ResultsThe animal study demonstrated that combinational administration of celecoxib with lactoferrin rescued the harmful effects caused by celecoxib in the treatment of tendon injury. Compared to tendon injury model group, 945 DEmRNAs, 7 DEmiRNAs and 34 DElncRNAs were obtained in celecoxib treatment group, and 493 DEmRNAs, 8 DEmiRNAs and 21 DElncRNAs were obtained in celecoxib + lactoferrin treatment group, respectively. Subsequently, 376 celecoxib + lactoferrin treatment group-specific DEmRNAs were determined. Then, 25 DEmRNAs associated with autophagy/hypoxia/ferroptosis/pyroptosis were identified.ConclusionsSeveral genes, such as, Ppp1r15a, Ddit4, Fos, Casp3, Tgfb3, Hspb1 and Hspa8, were identified to be associated with tendon injury and repair.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13018-023-03856-9.