Methanol (MeOH) is a promising low-carbon liquid fuel to provide global energy security with a potential to achieve net-zero greenhouse gas emissions in transport sector. However, its utilization in diesel engines at high MeOH substitution ratios (MSR) suffers from misfire or high pressure rise rates owing to its distinct physio-chemical properties. This issue is addressed in the present study by adopting negative-valve overlap (NVO) and hot residual gases from the previous cycle. Experiments are performed in a single-cylinder heavy-duty CI engine for a constant MSR (90% energy based) and an engine speed of 1500 rpm. The aim of the study is to investigate the effects of 1) NVO period, 2) charge-air temperature (Tair), 3) MeOH lambda (λMeOH) on the MeOH-diesel dual-fuel (DF) combustion in NVO mode, and 4) to demonstrate the implications of NVO in yielding high net-indicated efficiency (ηind) together with low pollutant emissions at a wide range of engine operating loads (40–90%). The results show that the hot residual gases from the previous cycle enhance the reactivity of the fresh MeOH-air mixture by inducing slow oxidation processes before TDCf. The slow pre-flame oxidation processes are disruptive or oscillatory in nature, wherein NVO period, Tair and λMeOH can be used to control these processes and their induced reactivity enhancing capability. It is noticed that the pre-flame oxidation processes and the main combustion have a direct correlation between them. Based on the control strategy, the MeOH-diesel combustion in the NVO mode produced on average ηind of approx. 53% accompanied with very low NOx emission of 1.1 g/kWh at a wide range of engine operating loads (40–90%). Additionally, on average the combustion phasing (CA50) is maintained at ∼ 2 oCA aTDC, while the combustion stability remains high (COVIMEP ∼ 3.5%).