About 655 million persons worldwide are affected by osteoarthritis (OA), associated with excruciating chronic pain and disability in the elderly. Inflammation and cell death are two key events in OA and also key canonical functions of caspases. Since caspases play an important role in modulating inflammation, pharmacological caspase inhibitors have been widely utilized to study diseases involving inflammation in animal models and clinical trials. Among these, key caspases, which are responsible for activation of the corresponding pathways, include caspase-8 for the receptor mediated apoptotic pathway and caspase-1 as the key inflammatory caspase being involved in OA pathogenesis. OA- and non-OA chondrocytes were treated with caspase-1 and -8 inhibitors and TNF-α. RNA was isolated after 3 days from three biological replicates (n = 3) of each group and processed for single-end RNA sequencing (1 × 114 bp). Data were pre-processed and analyzed with R programming language v4.2.2. Downstream analysis included identification of differentially expressed genes providing a comprehensive overview of unique and shared transcriptional changes in both OA and non-OA cohorts.