Backgrounds: Tension-Type Headache (TTH) is one of the most common types of headache. In patients with TTH, manual therapy can be used to treat myofascial pain. Objectives: This study aimed to evaluate the effect of manual therapy on TTH in patients who did not respond to drug therapy. Methods: A total of 24 patients with TTH were randomly enrolled into this prospective trial. The participants were divided into an intervention and a control group. The intervention group received the common medication and manual therapy, while the control group only received the common medication. Headache pain intensity, frequency, and duration, tablet count, and Neck Disability Index (NDI) were measured in both groups before, after, and one week after the intervention. Results: There were significant differences between the two groups (treatment, control) regarding pain intensity (3.04, 6.75, P = 0.0001; effect size (ES) = 1.85), headache frequency (2.33, 5, P = 0.004; ES = 1.48) and duration (91.29, 284.74, P = 0.002; ES = 1.48), tablet count (1.83, 4.91, P = 0.01; ES = 1.04), and NDI (7.33, 20.16, P = 0.003; ES = 1.37). Within group differences were recorded in intervention group only for all dependent variables immediately after intervention and one week after the intervention (p < 0.05). Conclusion: Manual therapy reduced headache pain intensity, frequency and duration, tablet count, and NDI score in patients with TTH.