Pharmaceutically active compounds (PhACs) represent an emerging class of contaminants. With a potential to negatively impact human health and the ecosystem, existence of pharmaceuticals in the aquatic systems is becoming a worrying concern. Antibiotics is a major class of PhACs and their existence in wastewater signifies a health risk on the long run. With the purpose of competently removing antibiotics from wastewater, cost-effective, and copiously available waste-derived adsorbents were structured. In this study, mango seeds kernel (MSK), both as a pristine biochar (Py–MSK) and as a nano-ceria-laden (Ce–Py–MSK) were applied for the remediation of rifampicin (RIFM) and tigecycline (TIGC). To save time and resources, adsorption experiments were managed using a multivariate-based scheme executing the fractional factorial design (FrFD). Percentage removal (%R) of both antibiotics was exploited in terms of four variables: pH, adsorbent dosage, initial drug concentration, and contact time. Preliminary experiments showed that Ce–Py–MSK has higher adsorption efficiency for both RIFM and TIGC compared to Py–MSK. The %R was 92.36% for RIFM compared to 90.13% for TIGC. With the purpose of comprehending the adsorption process, structural elucidation of both sorbents was performed using FT-IR, SEM, TEM, EDX, and XRD analyses which confirmed the decoration of the adsorbent surface with the nano-ceria. BET analysis revealed that Ce–Py–MSK has a higher surface area (33.83 m2/g) contrasted to the Py–MSK (24.72 m2/g). Isotherm parameters revealed that Freundlich model best fit Ce–Py–MSK–drug interactions. A maximum adsorption capacity (qm) of 102.25 and 49.28 mg/g was attained for RIFM and TIGC, respectively. Adsorption kinetics for both drugs conformed well with both pseudo-second order (PSO) and Elovich models. This study, therefore, has established the suitability of Ce–Py–MSK as a green, sustainable, cost-effective, selective, and efficient adsorbent for the treatment of pharmaceutical wastewater.