Objective To observe the preventive and therapeutic effects of scopolamine tablet and transdermal agent in combination with domperidone for seasickness in different voyage distances and sea state conditions. Methods A total of 236 participants were selected and batched for three trials (Trial 1: 80 sea miles voyage, 1-2 degree of sea state; Trial 2: 80 sea miles voyage, 3-4 degree of sea state; and Trial 3: 200 sea miles voyage, 3-4 degree of sea state). The motion sickness susceptibility questionnaire (MSSQ) was used to assess the seasickness susceptibility. The participants in each trial were divided into comprehensive medication group (CMG) receiving low dose oral and transdermal scopolamine in combination with oral domperidone, prophylactic medication group (PMG) receiving low dose oral and transdermal scopolamine, and placebo control group (PCG) receiving oral vitamine C. Motion sickness symptoms were evaluated by using Wiker rating scales. Results In trial 1, the Wiker scores and moderate seasickness incidence in the CMG and PMG were significantly lower than those in the PCG (P<0.05). No significant difference was observed in severe seasickness incidence rates among groups (P>0.05). In trial 2, the Wiker scores were significantly lower in the CMG than in the PCG (P<0.05). The incidence rates of severe seasickness were significantly decreased in CMG and PMG compared with PCG (P<0.05). No significant difference was observed in the moderate seasickness incidence rates among 3 groups (P>0.05). In trial 3, the Wiker scores were significantly lower in the CMG than in the PCG (P<0.05). The incidence rates of severe seasickness were significantly reduced in CMG and PMG compared with PCG (P<0.05). No significant difference was observed in the moderate seasickness incidence rates among 3 groups (P>0.05). Conclusion Low dose oral and transdermal scopolamine in combination with oral domperidone can alleviate seasickness symptoms and decrease incidence of severe seasickness during long-term voyage at sea.