Background Serial point-of-care ultrasound (PoCUS) can potentially improve acute patient care through treatment adjusted to the dynamic ultrasound findings. The objective was to investigate if treatment guided by monitoring patients with acute dyspnoea with serial cardiopulmonary PoCUS and usual care could reduce the severity of dyspnoea compared with usual care alone. Methods This was a randomised, controlled, blinded-outcome trial conducted in three EDs in Denmark between 9 October 2019 and 26 May 2021. Patients aged ≥18 years admitted with a primary complaint of dyspnoea were allocated 1:1 with block randomisation to usual care, which included a single cardiopulmonary PoCUS within 1 hour of arrival (control group) or usual care (including a PoCUS within 1 hour of arrival) plus two additional PoCUS performed at 2 hours interval from the initial PoCUS (serial ultrasound group). The primary outcome was a reduction of dyspnoea measured on a verbal dyspnoea scale (VDS) from 0 to 10 recorded at inclusion and after 2, 4 and 5 hours. Results There were 206 patients recruited, 102 in the serial ultrasound group and 104 in the control group, all of whom had complete follow-up. The mean difference in VDS between patients in the serial ultrasound and the control group was -1.09 (95% CI -1.51 to -0.66) and -1.66 (95% CI -2.09 to -1.23) after 4 and 5 hours, respectively. The effect was more pronounced in patients with a presumptive diagnosis of acute heart failure (AHF). A larger proportion of patients received diuretics in the serial ultrasound group. Conclusion Therapy guided by serial cardiopulmonary PoCUS may, together with usual care, facilitate greater improvement in the severity of dyspnoea, especially in patients with AHF compared with usual care with a single PoCUS in the ED. Serial PoCUS should therefore be considered for routine use to aid the physician in stabilising the patient faster. Trial registration number NCT04091334.