We present evidence for three spin-down glitches (or “anti-glitches”) in the ultraluminous accreting X-ray pulsar NGC 300 ULX-1, in timing observations made with the Neutron Star Interior Composition Explorer. Our timing analysis reveals three sudden spin-down events of magnitudes Δν = −23, −30, and −43 μHz (fractional amplitudes Δν/ν = −4.4, −5.5, and −7.7 × 10−4). We determined fully phase-coherent timing solutions through the first two glitches, giving us high confidence in their detection, while the third candidate glitch is somewhat less secure. These are larger in magnitude (and opposite in sign) than any known radio pulsar glitch. This may be caused by the prolonged rapid spin up of the pulsar, causing a sudden transfer of angular momentum between the superfluid and non-superfluid components of the star. We find no evidence for profile or spectral changes at the epochs of the glitches, supporting the conclusion that these are due to the same process as in normal pulsar glitches, but in reverse.