Background The Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQv2.1) is used to evaluate the impact of symptoms on the quality of life (QoL) of migraineurs. Objective To evaluate primarily the concurrent validity, test–retest reliability, and internal consistency, and secondarily the sensitivity to change of a Thai version of the MSQv2.1. Methods The original English version of the MSQv2.1 was translated into a Thai version. The Thai version of the MSQv2.1 was assessed for content and language equivalence. Validity of the Thai version of the MSQv2.1 was assessed using migraine characteristics in a prospective study conducted at the Chulalongkorn Comprehensive Headache Centre of King Chulalongkorn Memorial Hospital. Test–retest reliability and internal consistency were tested in migraineurs. Sensitivity to change was evaluated in another group of migraineurs using an 8-week follow-up. Results We recruited 30 migraineurs to test the validity, test–retest reliability, and internal consistency of the Thai version of the MSQv2.1 and 11 migraineurs to test its sensitivity to change. The Thai version of the MSQv2.1 scores were significantly correlated with migraine symptoms (inverse coefficient range from –0.62 to –0.39) except for associated symptoms, which had no correlation with any of the dimensions or overall QoL score. Spearman’s correlation coefficient for test–retest reliability was 0.56–0.83, and Cronbach’s α for internal consistency was 0.91–0.96. Headache, including average pain duration per attack, pain severity score (numeric rating scale), associated symptoms and dimensions, and overall QoL score of the Thai version of MSQv2.1 improved over time (P < 0.05). Moreover, improvement in headache correlated (coefficient range 0.67–0.77) with improvement in overall QoL score and some dimensions of the Thai version of the MSQv2.1 (coefficient range 0.66–0.77). Conclusion The Thai version of the MSQv2.1 had validity, acceptable internal consistency, moderate-to-strong test–retest reliability, and strong correlation between improvement in headache severity and overall QoL score. A future study with a larger sample size and longer follow-up is required for better estimates of internal consistency and sensitivity to change.