The fungi-based technology, wild-Serbian Ganoderma lucidum (WSGL) as myco-alternative to existing conventional microbial-based wastewater treatment is introduced in this study as a potential alternative treatment. The mycoremediation is highly persistent for its capability to oxidatively breakdown pollutant substrates and widely researched for its medicinal properties. Utilizing the non-hazardous properties and high degradation performance of WSGL, this research aims to find optimum conditions and model the mycoremediation treatment design for Chemical Oxygen Demand (COD) and Ammonia Nitrogen (AN) removal in domestic wastewater via response surface methodology (RSM). Combined process variables were temperature (⁰C) (Model 1) and the volume of mycelial pellets (%) (Model 2) against treatment time (hour). Response variables for these two sets of central composite design (CCD) were the removal efficiencies of COD (%) and AN (%). The regression line fitted well with the data with R2 values of 0.9840 (Model 1-COD), 0.9477 (Model 1-AN), 0.9988 (Model 2-COD) and 0.9990 (Model 2-AN). The lack of fit test gives the highest value of Sum of Squares equal to 9494.91 (Model 1- COD), 9701.68 (Model 1-AN), 23786.55 (Model 2-COD) and 13357.02 (Model 2-AN), with probability F values less than 0.05 showing significant models. The optimum conditions were established corresponding to the percentage of COD and AN removal obtained were 95.1% and 96.3%, accordingly at the optimum temperature 25°C at the treatment time of 24 h, meanwhile 0.25% of mycelial pellet with 76.0% and 78.4% COD and AN removal, respectively. The high performance achieved demonstrates that the mycoremediation of G. lucidum is highly potential as part of the wastewater treatment system in treating domestic wastewater of high organic loadings.