Actinomycetota are unrivalled producers of bioactive natural products, with strains living in association with macroalgae representing a prolific-yet largely unexplored-source of specialised chemicals. In this work, we have investigated the bioactive potential of Actinomycetota from macroalgae through culture-dependent and -independent approaches. A bioprospecting pipeline was applied to a collection of 380 actinobacterial strains, recovered from two macroalgae species collected in the Portuguese northern shore-Codium tomentosum and Chondrus crispus-in order to explore their ability to produce antibacterial, antifungal, anticancer and lipid-reducing compounds. Around 43% of the crude extracts showed activity in at least one of the screenings performed: 111 presented antimicrobial activity at 1 mg/mL, 83 significantly decreased cancer cells viability at 15 μg/mL and 5 reduced lipid content in zebrafish > 60% at 15 ug/mL. Dereplication of active extracts unveiled the presence of compounds that could explain most of the recorded results, but also unknown molecules in the metabolome of several strains, highlighting the opportunity for discovery. The bioactive potential of the actinobacterial community from the same macroalgae specimens, which served as the source for the aforementioned Actinomycetota collection, was also explored through metagenomics analysis, allowing to obtain a broader picture of its functional diversity and novelty. A total of 133 biosynthetic gene clusters recovered from metagenomic contigs and metagenome assembled genomes (MAGs). These were grouped into 91 gene cluster families, 83 of which shared less than 30% of similarity to database entries. Our findings provided by culture-dependent and -independent approaches underscore the potential held by actinomycetes from macroalgae as reservoirs for novel bioactive natural products.