Individuals with a spinal cord injury (SCI) are at an increased risk of developing cardiovascular disease and present with a multitude of elevated cardiometabolic component risks. Although upper-body exercise appears an effective strategy to improve some of these outcomes, the effectiveness of high-intensity interval training (HIIT) has yet to be determined for this population. Therefore, a randomized controlled trial will be conducted to determine the effectiveness of a 6 week home-based upper-body HIIT intervention on biomarkers of cardiometabolic health in persons with spinal cord injury, in comparison to a control (CON) group. We will recruit 40 individuals with chronic (>1 year post-injury) paraplegia (spinal cord lesion between the second thoracic and second lumbar vertebrae), aged between 18 and 65 years. After baseline testing, participants will be assigned randomly, using a 2:1 allocation, to the home-based exercise intervention (HIIT, n = 26) or control group (CON, n = 14). The HIIT intervention will consist of 30 min of arm crank-based HIIT (60 s intervals at 80–90% peak heart rate) four times per week. Participants in the CON group will be asked to maintain their habitual diet and physical activity patterns over the study period. Base-line and follow-up assessments will be made for determination of body composition, postprandial glycaemic control, fasting blood lipids and systemic inflammation, aerobic capacity, physical activity and energy intake, resting metabolic rate, resting blood pressure, and subjective measures of health and well-being. ClinicalTrials.gov, ID: NCT04397250. Registered on 21 May 2020.