HOmotypic fusion and Protein Sorting (HOPS) complex is a multi-subunit complex conserved from yeast to mammals that regulates late endosome-lysosome fusion. However, little is known about how HOPS complex is recruited to lysosomes in mammalian cells. Here we report that the small GTPase Arl8b, but not Rab7, is essential for membrane localization of hVps41 subunit of the HOPS complex. Assembly of the core HOPS subunits to Arl8b and hVps41-positive lysosomes is guided by their subunit-subunit interactions. RNAi-mediated depletion of hVps41 resulted in the impaired degradation of EGFR that was rescued upon expression of wild-type but not an Arl8b-binding defective mutant of hVps41, suggesting that Arl8b-dependent lysosomal localization of hVps41 is required for its endocytic function. Further, we have also identified that Arl8b effector SKIP/PLEKHM2 interacts with and recruits HOPS subunits to Arl8b and Kinesin–positive peripheral lysosomes. Accordingly, RNAi-mediated depletion of SKIP impaired lysosomal trafficking and degradation of EGFR. These findings reveal that Arl8b regulates association of the human HOPS complex with lysosomal membranes that is critical for the function of this tethering complex in endocytic degradation.