The introduction of novel, small-molecule Janus kinase inhibitors namely tofacitinib, baricitinib and upadacitinib has provided an alternative treatment option for patients with rheumatoid arthritis outside of traditional drugs and expensive biologics. This review aimed to critically assess the drug-drug interaction potential of tofacitinib, baricitinib and upadacitinib and provide a balanced perspective for choosing the most appropriate Janus kinase inhibitor based on the needs of patients with rheumatoid arthritis including co-medications and renal/hepatic impairment status. Based on the critical assessment, all three approved Janus kinase inhibitors generally provide a favourable opportunity for co-prescription with a plethora of drugs. While cytochrome P450 3A4-related inhibition or induction altered the exposures (area under the curve) of tofacitinib and upadacitinib, it did not impact the exposure of baricitinib. Transporter drug-drug interaction studies revealed that the disposition of baricitinib was altered with certain transporter inhibitors as compared with either tofacitinib or upadacitinib. Adjustment of tofacitinib or baricitinib dosages but not that of upadacitinib is required with the progression of renal impairment from a mild to a severe condition. While the dosage of tofacitinib needs to be adjusted for patients with moderate hepatic impairment status, it is not the case for either baricitinib or upadacitinib. Assessment of the drug-drug interaction potential suggests that tofacitinib, baricitinib and upadacitinib generally show a favourable disposition with no perpetrator activity; however, as victim drugs, they show subtle pharmacokinetic differences that may be considered during polypharmacy. Moreover, careful choice of the three drugs could be made in patients with rheumatoid arthritis with varying degrees of renal/hepatic impairments.