Antibiotic pollutants in aqueous solutions have major environmental and human health consequences such as toxicity to algae, disturbance in hormones, development of antibiotic resistance, growth inhibition, and increased human health risks. Therefore, efficient removal of it is essential. Adsorption-based antibiotic elimination is an effective and sustainable method. Among many, amoxicillin trihydrate is one of the most consumed antibiotics with approximately 80% residual. This study involves the removal of amoxicillin trihydrate from aqueous solutions using molybdenum disulfide (MoS2) nanosheets (first time used for amoxicillin). MoS2 nanosheets were synthesized through sonication-aided liquid-phase process. The characteristic peaks at 618 nm and 678 nm confirmed the presence of MoS2 nanosheets. SEM and EDX analysis supported the formation of nanosheets. UV–visible spectrophotometer was used for method validation which showed 0.31 standard deviation and 0.76%RSD. The limit of detection was 1.2 mg/L and limit of quantification was 3.7 mg/L. Optimization of adsorption parameters was performed using response surface design of experiment. The results (quadratic model and ANOVA) of optimization parameters showed that dose of MoS2 had significant effect on RE%. The optimized parameter values were 1.5 mg/mL (adsorbent dosage), 10.2 (pH), 45.2 µg/mL (initial amoxicillin concentration), and 20 min (contact time) for 98% removal efficiency. Isotherm study showed the adsorption mechanism was monolayered, exothermic, and spontaneous. In addition, the amoxicillin adsorption kinetics was well represented using a pseudo-second-order model.