Objective: To assess the efficacy and safety of upadacitinib, an oral Janus kinase inhibitor, as monotherapy or in combination with non-biologic DMARDs (nbDMARDs) in patients with PsA. Methods: Pooled data were analysed from patients with prior inadequate response or intolerance to ≥ 1 nbDMARD (SELECT-PsA 1) or ≥ 1 biologic DMARD (SELECT-PsA 2) who received placebo, upadacitinib 15 mg once daily (QD), or upadacitinib 30 mg QD as monotherapy or in combination with ≤2 nbDMARDs for 24 weeks. Efficacy outcomes included achievement of American College of Rheumatology responses, Psoriasis Area and Severity Index responses, and minimal disease activity, and change from baseline and clinically meaningful improvement in Health Assessment Questionnaire-Disability Index. Adverse events (AEs) were summarized. Results: 1916 patients were included; 574 (30%) received monotherapy and 1342 (70%) received combination therapy. Placebo-subtracted treatment effects (95% CI) for ACR20 at week 12 were 33.7% (24.4–43.1) and 34.0% (27.9–40.1) for upadacitinib 15 mg QD monotherapy and combination therapy, respectively, and 45.7% (36.9–54.5) and 39.6% (33.7–45.5) for upadacitinib 30 mg QD monotherapy and combination therapy, respectively. Treatment effects for other outcomes were consistent between monotherapy and combination therapy. AE frequency was generally similar for upadacitinib monotherapy and combination therapy, although hepatic disorders and creatine phosphokinase elevation were more common with combination therapy vs monotherapy. Conclusion: The efficacy and safety of upadacitinib were generally consistent when administered as monotherapy or in combination with nbDMARDs through 24 weeks, supporting the use of upadacitinib with or without nbDMARDs in PsA.