The Mekong River ranks within the top ten rivers of the world in terms of water discharge and sediment load to the ocean, yet its organic matter (OM) composition remains unstudied. This river is experiencing anthropogenically forced changes due to land use and impoundment, and these changes are expected to intensify in the future. Accordingly, we monitored the composition (including vascular-plant signatures) of Mekong River fine particulate organic matter (FPOM) over a one-year period. Autochthonous production comprises a greater proportion of FPOM during the dry season than in the rainy season, as demonstrated by higher percent organic carbon values (7.9 ± 2.4 versus 2.2 ± 0.4%), lower yields of lignin normalized to carbon (0.40 ± 0.05 versus 1.1 ± 0.3 mg (100 mg OC)−1), and an increase in N:C ratios toward phytoplankton values during the dry season (from 0.06 to 0.12). Changes in the lignin-phenol composition of FPOM suggest that gymnosperms contribute more toward FPOM composition during the dry season, with angiosperms dominating in the wet season. This is supported by calculations of the lignin phenol vegetation index of riverine FPOM, which increases between the dry to wet seasons (dry: 29.4 ± 15.0 versus wet: 74.6 ± 17.3). These changes likely reflect seasonal differences in the proportion of flow that is coming from the Upper and Lower Basin, corresponding to compositional differences between the vegetation of these regions. Therefore, this work provides a baseline understanding of FPOM variability that can be used to assess how future change will affect this river.