Two new secoiridoid glucosides, namely iso-oleonuezhenide (1) and methyloleoside 7-ethyl ester (2), along with five known ones, oleonuezhenide (3), nuezhenide (4), oleuropein (5), G13 (6), and jaspolyside methyl ester (7), were isolated from the fruits of Ligustrum lucidum. Their structures were assigned based on 1H-NMR, 13C-NMR, and 2D-NMR analyses, in combination with HR-MS experiments and the comparison with literature data of related compounds, as well as on chemical experiments. We have examined the ability of these compounds to activate ERK and CREB in cultured cortical neurons. Our studies demonstrate that compound 1 induces ERK and CREB phosphorylation in primary cortical neurons in a dose- and temporal-dependent manner, suggesting its bioactivity on neurons.