In a Globular Cluster (GC), the mass loss during the red giant branch (RGB) phase and the helium content are fundamental ingredients to constrain the horizontal-branch (HB) morphology. While many papers have been dedicated to the helium abundance in different stellar populations, small efforts have been made to disentangle the effects of mass loss and helium content. We exploit the nearby GC NGC 6121 (M4), which hosts two well-studied main stellar populations, to infer both helium and RGB mass loss. We combine multi-band Hubble Space Telescope photometry of RGB and main-sequence (MS) stars of M4 with synthetic spectra to constrain the relative helium content of its stellar populations. We find that the second-generation stars in M4 are enhanced in helium mass fraction by {{∆ }}Y=0.013+/- 0.002 with respect to the remaining stars that have pristine helium content. We then infer the mass of the HB stars by searching for the best match between the observations and HB populations modeled assuming the helium abundance of each population estimated from the MS. By comparing the masses of stars along the HB, we constrain the mass loss of first- and second-generation stars in M4. We find that the mass lost by the helium-enriched population is ̃13% larger than the mass lost by the first-generation stars ({{∆ }}μ =0.027+/- 0.006 {M}☉ ). We discuss the possibility that this mass-loss difference depends on helium abundance, the different formation environment of the two generations, or a combination of both.