Cancer and associated medical treatments affect patients' health-related quality of life (HRQoL) by decreasing functional dimensions of physical, social, cognitive, and emotional well-being, while increasing short and late-term symptoms. Exercise, however, is demonstrated to be a useful therapy to improve cancer patients' and survivors' HRQoL, yet the effectiveness of high-intensity training (HIT) exercise is uncertain. This systematic review and meta-analysis aimed to analyse the effects of HIT on HRQoL dimensions in cancer patients and survivors as well as evaluate the optimal prescription of HIT. The search followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) and examined Web of Science and PubMed (Medline) databases. Data were analysed utilizing Review Manager Software. Twenty-two articles were included in the systematic review and 17 in the meta-analysis. Results showed HIT improved global quality of life, physical functioning, role functioning, social functioning, cognitive functioning, fatigue, pain, dyspnea, and insomnia, compared to an inactive control group, yet no differences were found between HIT and low to moderate-intensity exercise interventions. Particular improvements in HRQoL were observed during cancer treatment and with a training duration of more than eight weeks, a frequency of 2 days/week, and a volume of at least 120 min/week, including 15 min or more of HIT. Our findings whilst encouraging, highlight the infancy of the extant evidence base for the role of HIT in the HRQoL of cancer patients and survivors.