Determining the optimum levels of macroalgal density and salinity for removing aquaculture effluent has gained increasing research interest in recent years because of the growing concerns over environmental sustainability. Here, we determined the effects of macroalgal density and salinity on the uptake of NO2−, NO3−, NH3, and PO43− by Caulerpa lentillifera from the effluent of Poecilia latipinna using spectrophotometry. Laboratory experiments were conducted to measure nutrient uptake at five different macroalgal density levels (10, 20, 30, 40, and 50 g/L) and three salinity levels (20, 30, and 40 ppt) with and without aeration. Quadratic regression analysis revealed significant nonlinear and linear effects of macroalgal density on the uptake of NO2−, NO3−, NH3, and PO43−, where the maximum uptake was predicted to occur at the macroalgal densities of 31.6, 33.3, 50.0, and 20.0 g/L, respectively. Likewise, the effects of salinity on the uptake of NO2−, NO3−, NH3, and PO43− were significant and nonlinear where the maximum uptake was predicted to occur at the salinity levels of 29.1, 30.7, 29.5, and 29.5 ppt, respectively. The result of the effects of aeration was mixed but somewhat indicated a positive effect on the nutrient uptake within the 24 h period. Our results could help aquaculturists to minimize the excessive nutrients by C. lentillifera from aquaculture effluent while achieving long-term sustainable aquaculture production.