Mitochondrial dysfunction has been implicated in many neurodegenerative diseases, such as Parkinson’s disease, and mitoprotective metabolites may hold the key to potentially effective treatments. In this study, comprehensive chemical investigation of an Australian marine sponge, Aaptos lobata, led to the isolation of three new aaptamine-type 1H-benzo[de][1,6]-naphthyridine alkaloids, namely 3,6′-diaaptamine (2), aaptanone A (3) and 8-demethylaaptamine (4), alongside four known compounds, 8,8′,9,9′-tetramethoxy-1H,1′H-3,3′-bibenzo[de][1,6]naphthyridine (5), aaptanone (6), 9-methoxy-N-demethylaaptanone (7) and aaptamine (1). The structures of these compounds were determined using an analysis of spectroscopic data. Biological evaluation in SH-SY5Y using 6-OHDA as neurotoxin revealed that compounds 2, 3, 4, 5 and 7 displayed potent mitoprotective activity, effectively attenuating cell death with apparent EC50 values ranging from 0.05 μM to 1.06 μM. These compounds also mitigated mitochondrial membrane depolarization with apparent EC50 values between 0.021 μM and 0.78 μM. These findings highlight the therapeutic potential of A. lobata-derived alkaloids as promising candidates for mitochondria-targeted drug development.