Cancer is a major global health concern, affecting nearly 20 million individuals annually, according to the International Agency for Research on Cancer (IARC). There are some unconventional and conventional treatments for cancer. Typically, they span a wide spectrum of conventional and advanced therapeutic approaches, such as photodynamic therapy (PDT). This has long been valued for its non-invasive, targeted, and minimally toxic approach in the management of cancer. More importantly, PDT results in fewer operative and post-operative major complications, faster recovery times, reduced operating time, and saved costs. There are two types of photosensitizers in PDT, including synthetics (e.g., hematoporphyrin derivative, photofrin II, verteporfin) and natural (e.g., Hypocrellin A (HA) and Hypocrellin B (HB)). Nine electronic databases—WanFang Data, PubMed, ScienceDirect, Scopus, Web of Science, Springer Link, SciFinder, and the China National Knowledge Infrastructure (CNKI)—were systematically searched for this review, covering the literature published within the past 20 to 30 years (time range), without language restrictions. Studies were included if they were identified using the keywords Hypocrellin A, Hypocrellin B, photodynamic therapy, and cancer (inclusion criteria). All eligible papers were collected, critically analyzed, and summarized. Duplicate records were excluded during the screening process (exclusion criteria). HA and HB, derived from the fungus Hypocrella bambusae, offer a natural alternative with lower toxicity. However, these compounds are still in the in vitro or in vivo, and must meet rigorous standards for “quality”, “safety”, “efficacy”, “pharmacokinetics”, as well as “regulatory compliance” before entering clinical trials. “Curcumin” is a successful PS for traditional Chinese medicine used in PDT during clinical study and it is used as a benchmark for HB. Currently, scientists are paying attention to “nanotechnology” that enhances hypocrellin’s properties in PDT for achieving clinical goals, but further investigations are required.