Fucoidans from Laminaria hyperborea (LH) can be antioxidative, antiangiogenic, and anti-inflammatory. In this study, a very high-molecular weight (3700 kDa) fucoidan from LH, FucBB04, was tested regarding its bioactivity in age-related macular degeneration (AMD) models in vitro. Primary retinal pigment epithelium (RPE) from pig eyes, human uveal melanoma cell line OMM-1, and RPE cell line ARPE-19 were used. Substituents of the extract were determined with chemical analysis. Cell viability was tested with tetrazolium assay (MTT), oxidative stress was induced by H2O2 or erastin, respectively. Secreted vascular endothelial growth factor A (VEGF-A) was assessed with ELISA. Retinal pigment epithelium 65 kDa protein (RPE65) and protectin (CD59) protein expression were tested in Western blot. Cell barrier was assessed by measuring trans-epithelial electrical resistance (TEER), phagocytic ability by a fluorescence assay. Gene expression and secretion of interleukin 6 (IL-6) and interleukin 8 (IL-8) were tested in real-time PCR and ELISA. FucBB04 displayed no oxidative stress protective effects. Its effect on VEGF was inconsistent, with VEGF secretion reduced in primary RPE, but not in ARPE-19. On the other hand, Lipopolysaccharide (LPS) and polyinosinic/polycytidylic acid (PIC)-induced IL-6 or IL-8 secretion was reduced by FucBB04, while complement inhibiting protein CD59 was not affected. In addition, FucBB04 did not influence the gene expression of IL-6 or IL-8. Visual cycle protein RPE65 expression, phagocytic ability, and barrier function were reduced by FucBB04. Very high-molecular weight fucoidan from LH shows bioactivities against AMD-related pathological pathways, but adverse effects on RPE function may limit its suitability as a therapeutic compound. Smaller high-molecular weight fucoidans are recommended for further research.