The present study was undertaken to evaluate the antimicrobial, antioxidant, and anticancer activity of Dirinaria aegialita (Afzel. ex Ach.) B.J. Moore and Parmotrema praesorediosum (Nyl.) Hale, the two dominant macrolichens taxa from the Similipal Biosphere Reserve of Odisha. Both the lichens were evaluated for their efficacy against three bacterial species such as Staphylococcus aureus, Pseudomonas aeruginosa, and Bacillus subtilis, and three fungal species such as Aspergillus niger, Trichoderma harzianum, and Candida albicans. The D. aegialita and P. praesorediosum showed higher inhibitory effect against Bacillus subtilis and Staphylococcus aureus, respectively. D. aegialita also showed the higher inhibitory activity against MCF-7 and MDA MB-231 breast cancer cell line as compared to P. praesorediosum. Besides, D. aegialita was found to have better antioxidant activity than P. praesorediosum in scavenging assay. Thus, the results of the above study confirmed that D. aegialita species is having better potential in its antibacterial, antioxidant, and anticancer activity as compared to P. praesorediosum.