Abstract The emission region of γ-ray bursts (GRBs) is poorly constrained. The uncertainty on the size of the dissipation site spans over 4 orders of magnitude (10¹²–10¹⁷ cm) depending on the unknown energy composition of the GRB jets. The joint multiband analysis from soft X-rays to high energies (up to ∼1 GeV) of one of the most energetic and distant GRBs, GRB 220101A (z = 4.618), allows us to make an accurate distinction between prompt and early afterglow emissions. The enormous amount of energy released by GRB 220101A (E _iso ≈ 3 × 10⁵⁴ erg) and the spectral cutoff at E cutoff = 85 − 26 + 16 MeV observed in the prompt emission spectrum constrain the parameter space of the GRB dissipation site. We put stringent constraints on the prompt emission site, requiring 700 < Γ₀ < 1160 and R _γ ∼ 4.5 × 10¹³ cm. Our findings further highlight the difficulty of finding a simple self-consistent picture in the electron–synchrotron scenario, favoring instead a proton–synchrotron model, which is also consistent with the observed spectral shape. Deeper measurements of the time variability of GRBs, together with accurate high-energy observations (MeV–GeV), would unveil the nature of the prompt emission.