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Injuries to flexor tendons can be complicated by fibrotic adhesions, which severely impair the function of the hand. Plasminogen activator inhibitor 1 (PAI‐1/SERPINE1), a master suppressor of fibrinolysis and protease activity, is associated with adhesions. Here, we used next‐generation RNA sequencing (RNA‐Seq) to assess genome‐wide differences in messenger RNA expression due to PAI‐1 deficiency after zone II flexor tendon injury. We used the ingenuity pathway analysis to characterize molecular pathways and biological drivers associated with differentially expressed genes (DEG). Analysis of hundreds of overlapping and DEG in PAI‐1 knockout (KO) and wild‐type mice (C57Bl/6J) during tendon healing revealed common and distinct biological processes. Pathway analysis identified cell proliferation, survival, and senescence, as well as chronic inflammation as potential drivers of fibrotic healing and adhesions in injured tendons. Importantly, we identified the activation of PTEN signaling and the inhibition of FOXO1‐associated biological processes as unique transcriptional signatures of the healing tendon in the PAI‐1/Serpine1 KO mice. Further, transcriptomic differences due to the genetic deletion of PAI‐1 were mechanistically linked to PI3K/Akt/mTOR, PKC, and MAPK signaling cascades. These transcriptional observations provide novel insights into the biological roles of PAI‐1 in tendon healing and could identify therapeutic targets to achieve scar‐free regenerative healing of tendons. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:43–58, 2020 [ABSTRACT FROM AUTHOR]