The rapid increase in biomass and plastic waste poses significant environmental challenges. Co-pyrolysis of biomass with plastic wastes offers a promising avenue for sustainable waste management and renewable energy generation. This study covers several novel aspects: First, it investigates the impacts of feedstock composition and operating conditions in pyrolysis (individual feedstock) and co-pyrolysis (biomass and plastic wastes). The study reveals that synergistic effects, specifically improved yields and optimized temperature, exist in the co-pyrolysis of biomass and plastic wastes compared to individual feedstock. Secondly, a suitable blended machine learning predictive model (with Random Forest, Gradient Boosting Regressor, and XGBoost) and robust optimization framework are developed to address model accuracy, non-linear interactions, and uncertainties in pyrolysis such as temperature, heating rate, and biomass-to-plastic ratio. This study predicts the bio-oil yield quantitatively (amount) and qualitatively (composition) with high accuracy (R2 > 0.97). Thirdly, key factors contributing to yield include plastic content (18 %) and biomass type (13 %) have been identified through Gini feature importance and Shapley Additive Explanation (SHAP) analysis. Furthermore, multi-objective optimization techniques reveal the most optimal bio-oil yield under specific conditions, supported by uncertainty analysis, which confines bio-oil yield to a range of 30–50 %. Finally, it also demonstrates a case study to find the optimal bio-oil yield and quality conditions using co-pyrolysis of local resources, i.e., biomass (wood and bagasse) and plastic wastes. The case study suggests optimal conditions like > 50 °C heating rate, <50 min pyrolysis time, and > 60 % plastic content in a blend of wood and HDPE. This study assists industries and policymakers to assess and understand the viability of co-pyrolysis, optimal design parameters, and process impacts.