The cost of substrates has been one of the challenges for mushroom cultivation. The commonly used substrates for mushroom production are usually expensive. Substrates with a high biomass return that can pose environmental problems can be good alternatives for mushroom cultivation due to multiple advantages. In this regard, the potential use of water hyacinth biomass (a troublesome aquatic weed) as an alternative substrate is worthy of being studied. This study was aimed at evaluating the potential use of water hyacinth biomass for the production of oyster mushroom. The experiment was done in a completely randomized design with nine treatments and four replications. Water hyacinth biomass was supplemented with straw (wheat, Triticum aestivum, and teff or Eragrostis Teff) at a ratio of 1 : 1, 1 : 3, or 3 : 1. The developmental parameters including days elapsed for mycelium invasion (MI), pinhead formation (PF), and the first flush (FH) were monitored. Growth parameters (cap diameter (CD) and stalk length (SL)), a yield parameter (total weight of mushroom yield), and biological efficiency (BF %) were also recorded. Finally, the economic return (ER) of all the treatments was calculated. A one-way analysis of variance (ANOVA) was used to test the significance of variation between the different parameters on the production parameters. Means were separated using the Tukey test, when F-test from ANOVA was significant at p ≤ 0.05 . It was observed that water hyacinth biomass alone or supplemented with wheat or teff straw provided promising performance on oyster mushroom development, growth, yield, and biological efficiency compared to the costly substrates (wheat and teff straw). Thus, water hyacinth can be considered as a low-cost substrate for mushroom cultivation and a means to control this aquatic weed from rapid spreading.