The study investigated healthcare expenditure from the perspective of cancer patients, to determine the level of Catastrophic Health Expenditure (CHE) and its associated factors. This cross-sectional study was conducted in three Malaysian public hospitals namely Hospital Kuala Lumpur, Hospital Canselor Tuanku Muhriz and the National Cancer Institute using a multi-level sampling technique to recruit 630 respondents from February 2020 to February 2021. CHE was defined as incurring a monthly health expenditure of more than 10% of the total monthly household expenditure. A validated questionnaire was used to collect the relevant data. The CHE level was 54.4%. CHE was higher among patients of Indian ethnicity (P = 0.015), lower level education (P = 0.001), those unemployed (P < 0.001), lower income (P < 0.001), those in poverty (P < 0.001), those staying far from the hospital (P < 0.001), living in rural areas (P = 0.003), small household size (P = 0.029), moderate cancer duration (P = 0.030), received radiotherapy treatment (P < 0.001), had very frequent treatment (P < 0.001), and without a Guarantee Letter (GL) (P < 0.001). The regression analysis identified significant predictors of CHE as lower income aOR 18.63 (CI 5.71-60.78), middle income aOR 4.67 (CI 1.52-14.41), poverty income aOR 4.66 (CI 2.60-8.33), staying far from hospital aOR 2.62 (CI 1.58-4.34), chemotherapy aOR 3.70 (CI 2.01-6.82), radiotherapy aOR 2.99 (CI 1.37-6.57), combination chemo-radiotherapy aOR 4.99 (CI 1.48-16.87), health insurance aOR 3.99 (CI 2.31-6.90), without GL aOR 3.38 (CI 2.06-5.40), and without health financial aids aOR 2.94 (CI 1.24-6.96). CHE is related to various sociodemographic, economic, disease, treatment and presence of health insurance, GL and health financial aids variables in Malaysia.