Background: Herbal supplements (HS) are one of the most commonly used complementary and alternative medicines in cancer. Reduced therapeutic efficacy of prescription anticancer agents through unwarranted herb–drug interactions is a major efficacy/safety concern. In view of the rising cancer prevalence in India along with a high degree of reliance and cultural acceptability in favor of traditional medicine drugs, prevalence data exclusively of HS usage during cancer treatment are of considerable epidemiological significance. Methodology: This questionnaire-based prospective observational study aimed at estimating the prevalence of HS among cancer patients during treatment at our tertiary care medical center. Taken on a population of 220 patients within a period of 9 months, data were generated by a customized validated questionnaire and the same processed by IBM SPSS Statistics for Windows, version XXIV, Armonk, NY: IBM Corp. Differences between HS use and nonuse with respect to demographic, disease, and treatment characteristics were assessed by Chi-square test. For examining the latter variables as possible predictors of HS usage, they were entered into bivariate logistic regression with odds ratio and confidence intervals calculated for each. Results: Out of 220 patients, 57 (26%) were HS users and 163 (74%) were nonusers. Majority of the users (42.1%) were on self-prepared folklore herbal medicine postdiagnosis of cancer (57.9%), the most common reason cited being symptom palliation (35.1%) on the advice of friends and family (64.9%). Fear of disapproval was the most common reason cited (68.4%) for not disclosing HS usage to the physician. Conclusion: Chemotherapy and unemployment are predictors of HS usage, and there is a significant association between occupation status and HS usage. This first study on HS prevalence among South Indian population proposes the need for a more robust evidence base for understanding all aspects of HS use in cancer.