Background: Out-of-pocket costs pose a substantial economic burden to cancer patients and their families. The purpose of this study was to evaluate the literature on out-of-pocket costs of cancer care. Methods: A systematic literature review was conducted to identify studies that estimated the out-of-pocket cost burden faced by cancer patients and their caregivers. The average monthly out-of-pocket costs per patient were reported/estimated and converted to 2018 USD. Costs were reported as medical and non-medical costs and were reported across countries or country income levels by cancer site, where possible, and category. The out-of-pocket burden was estimated as the average proportion of income spent as non-reimbursable costs. Results: Among all cancers, adult patients and caregivers in the U.S. spent between USD 180 and USD 2600 per month, compared to USD 15–400 in Canada, USD 4–609 in Western Europe, and USD 58–438 in Australia. Patients with breast or colorectal cancer spent around USD 200 per month, while pediatric cancer patients spent USD 800. Patients spent USD 288 per month on cancer medications in the U.S. and USD 40 in other high-income countries (HICs). The average costs for medical consultations and in-hospital care were estimated between USD 40–71 in HICs. Cancer patients and caregivers spent 42% and 16% of their annual income on out-of-pocket expenses in low- and middle-income countries and HICs, respectively. Conclusions: We found evidence that cancer is associated with high out-of-pocket costs. Healthcare systems have an opportunity to improve the coverage of medical and non-medical costs for cancer patients to help alleviate this burden and ensure equitable access to care.