The change of fluvial suspended sediment concentration (SSC) to the sea directly reflects the effects of riverine anthropogenic activities and natural force. Based on long-term hydrological data at Tarbert Landing Station of the Mississippi River (MR), statistical means, such as percentile method and Mann-Kendall method are used to detect change process of SSC from the MR entering the Gulf of Mexico in recent 40 years, and associated possible influencing factors. The results show that: (1) SSC from the MR entering the Gulf of Mexico is characterized by a staged decline from 1976 to 2015, in the first stage from 1976 to 1987, the SSC is relatively high with an average value of 0.33 kg/m³; in the second stage from 1988 to 2015, the SSC is much lower with a mean value of 0.25 kg/m³. (2) The relationship between daily SSC and runoff of MR follows Gaussian distribution. Compared with the first stage (1976−1987), the rating curve between SSC and runoff in the second stage (1988−2015) is relatively flat, when the number of high daily SSC event over 0.60 kg/m³ reduces significantly. SSC increases with the runoff in low-action flows and reaches the maximum when the runoff approaches 20 000 m³/s, but decreases with the runoff thereafter. The rating curve between monthly SSC and water discharge of the MR exhibits “double-loop” shape during 1976−1987, but presents clockwise “single loop” with “sediment before water” during 1988−2015. (3) Flood diversion project construction and soil conservation measures dominate the fluvial SSC from the MR into the Gulf of Mexico. The construction of flood diversion engineering reduces the sediment source along the river channel, and the soil conservation measures repress the land erosion, which have combined to keep the SSC at a relatively low level. In addition, SSC in the MR presents minor response to extreme hydrological events.