Introduction: Triterpenoid-based standardized Centella asiatica leaves extract as nasal solution (INDCANS) has shown potential in animal models of stress-related disorders. Objective: Efficacy and safety evaluation of INDCA-NS in patients with Tension-type headache (TTH). Methods: Ninety-one patients with TTH were randomized and administered INDCA-NS (46 patients) or PLACEBOCA-NS (45 patients) nasal spray (400 μg/day, 100 μg in 100 μL shot/ nostril, twice daily) for 28 days, with a 14-day follow-up. Efficacy (headache duration, frequency, and intensity; 21-item “Depression, Anxiety, and Stress Scale” (DASS-21); “Work Productivity and Activity Questionnaire” (WPAI: SHP); “World Health Organization Brief” (WHOQOL-BREF), cortisol and DHEA levels, rescue medications), and safety outcome measures (including adverse events) were monitored. Results: Subacute administration of INDCA-NS (but not PLACEBOCA-NS) significantly reduced the duration of headache and TTH's effect of TTH on WPAI:SHP (Q5) scores, namely productivity in working patients (P < 0.05, within the groups). The INDCA-NS showed significant difference (P < 0.05) in headache duration with and without covariate adjustment (vs. PLACEBOCA-NS). Both treatments found safe, well- tolerated, with no treatment-related adverse events, significantly reduced headache frequency, pain intensity, DASS-21 (stress domain), TTH's impact on daily activities (Q6 of WPAI:SHP), and improved WHOQOL scores (P < 0.05, within the group). The other outcome measures were not statistically significant within or between groups. Conclusion: Subacute INDCA-NS reduced headache duration and improved work productivity in TTH patients.