This paper presents the results of experimental investigation of the effects of milling methods (up-milling and down-milling) and cooling strategies [emulsion cooling, minimum quantity lubrication (MQL), cryogenic cooling using liquid nitrogen (LN 2) and combined (MQL + LN 2)] on flank wear, chip morphology and surface roughness in peripheral high speed end-milling of Inconel-718. The experimental results show that down-milling generated lower maximum flank wear than up-milling for all cooling strategies, thus improves machinability. MQL cooling with down-milling generated lowest maximum flank wear of 0.072 mm after eight passes and is recommended for machining Inconel-718, whereas LN 2 cooling with up-milling generated highest flank wear of 1.984 mm after first pass only. Tool wear mechanism in up-milling is adhesion and failure modes are chipping and plastic deformation, causing rapid tool wear, while abrasion is the tool wear mechanism under down-milling causing progressive tool wear. Also, emulsion up-milling generated lowest surface roughness of 0.29 μm, whereas emulsion, MQL and combined (MQL + LN 2) cooling strategies with down-milling generated equal and second lowest surface roughness of 0.34 μm. Results show that using MQL cooling under down-milling for machining Inconel-718 can lead to significant cost saving and sustainable machining.