Introduction: Ankylosing spondylitis (AS) presents challenges in selecting first-line biologic disease-modifying anti-rheumatic drugs (b-DMARDs) due to uncertainty about their effectiveness. Additionally, new research has introduced targeted synthetic DMARDs (ts-DMARDs) as treatment options. This systematic review compares the effectiveness of various DMARDs, both biologic and targeted, for AS patients.Materials and methods: A literature search was performed in several databases with the keywords “ankylosing spondylitis”, “DMARDs”, “efficacy”, and “network meta-analysis” with its synonym applied. Inclusion criteria were network meta-analysis (NMAs), ≥18-year-old patients with AS, and language in Bahasa or English. Critical appraisal of selected NMAs was carried out according to the ISPOR guideline for NMA. This study is registered in PROSPERO with the ID of CRD42024563670. Results: Eleven NMAs based on randomized clinical trials were included. Infliximab was found to have the greatest probability of eliciting a response across various assessments (ASAS 20, ASAS 40, BASDAI 50, and BASFI). Among subcutaneous biologics, Golimumab demonstrated the highest probability of response. The evidence for ts-DMARDs, such as JAK inhibitors, indicates they may be viable alternatives if established treatments do not achieve remission. However, these results should be interpreted with caution due to statistical insignificance in several NMAs, likely from limited direct comparisons between DMARDs. Conclusion: Infliximab appears to have a higher likelihood of achieving responses in various assessments, and Golimumab may be considered for those preferring subcutaneous administration. Both treatments may be promising options for first-line therapy, but these conclusions should be viewed cautiously until future RCTs provide more robust comparative data on DMARDs. © 2025 Universiti Putra Malaysia Press. All rights reserved.