Cancer is a silent killer and remains to pose major health problems globally. Amongst the several biological targets, DNA is one of the most striking targets in cancer chemotherapy. Owing to its planar structure, phenanthrene and its derivatives exhibit potential cytotoxicity by intercalating between the DNA base pairs and by inhibiting the enzymes that are involved in the synthesis of DNA. However, due to the off-target effects and resistance, the development of novel chemotherapeutic agents would be meritorious. In this regard, we present a detailed review on the development of phenanthrene-based derivatives reported in the last quinquennial. This review mainly focuses on the synthetic aspects and strategies to procure the fused phenanthrene derivatives such as (i) phenanthroindolizidines, phenanthroquinolizidine, phenanthroimidazoles, podophyllotoxin-based phenanthrenes, and dihydrophenanthrodioxine derivatives, (ii) phenanthrene conjugates with other pharmacologically significant pharmacophores, and (iii) phenanthrene-metal complexes. This review also edifies their potential in vitro cytotoxicity evaluation against various carcinoma cell lines in submicromolar to nanomolar ranges. Additionally, computational studies and structure-activity relationships (SARs) have also been presented to highlight the essential features of the designed congeners. Thus, this review would aid in the development of novel derivatives in future as potential cytotoxic agents in the field of medicinal chemistry.