Profundal lake sediment is an important site of toxic methylmercury (MeHg) production by anaerobic bacteria including sulfate-reducing bacteria (SRB). This study tracked sediment MeHg production, release and degradation in hypereutrophic Hodges Reservoir, USA. Sediment-associated MeHg was elevated in the early spring, suggesting production in profundal sediment during moderately reduced conditions. Later in the spring, sediment MeHg was released into hypolimnetic water, coincidental with the loss of bioavailable iron-oxides, suggesting iron-oxide dissolution led to the co-release of organic matter-associated MeHg. SRB activity in the late spring and early summer, as demonstrated by a drop in porewater sulfate, was associated with sediment buildup of MeHg, likely due to enhanced sorption to biogenic sulfides and organic matter. In the fall, sediment MeHg decreased, potentially a result of demethylation by methanogenic bacteria. Shortly afterwards, MeHg increased in the hypolimnetic water column, indicating an upward shift in the zone of SRB methylation. Our study suggests two “hot moments” of MeHg entry into the water column where it is susceptible to uptake into the pelagic food web: a spring window of mildly reduced conditions that promote MeHg release from sediment, and a fall window where MeHg is produced in the upper hypolimnetic water column.