diff --git a/.github/workflows/ci.yml b/.github/workflows/ci.yml
index 06e63df..bebecbe 100644
--- a/.github/workflows/ci.yml
+++ b/.github/workflows/ci.yml
@@ -54,6 +54,31 @@ jobs:
       - run: cargo test --all-features
         if: matrix.rust == 'nightly'
 
+  test-be:
+    name: Test Big-Endian
+    runs-on: ubuntu-latest
+    timeout-minutes: 30
+    strategy:
+      fail-fast: false
+      matrix:
+        target: [mips-unknown-linux-gnu, mips64-unknown-linux-gnuabi64]
+    steps:
+      - uses: actions/checkout@v4
+      - uses: dtolnay/rust-toolchain@nightly
+      - uses: taiki-e/setup-cross-toolchain-action@v1
+        with:
+          target: ${{ matrix.target }}
+
+      - name: Enable type layout randomization
+        run: echo RUSTFLAGS=${RUSTFLAGS}\ -Zrandomize-layout >> $GITHUB_ENV
+
+      - uses: Swatinem/rust-cache@v2
+
+      - run: cargo build -Zbuild-std
+      - run: cargo test -Zbuild-std
+      - run: cargo build --no-default-features -Zbuild-std
+      - run: cargo test --no-default-features -Zbuild-std
+
   miri:
     name: miri ${{ matrix.flags }}
     runs-on: ubuntu-latest
diff --git a/Cargo.toml b/Cargo.toml
index 796fbc8..e80f0ca 100644
--- a/Cargo.toml
+++ b/Cargo.toml
@@ -18,6 +18,7 @@ smallvec = { version = "1.0", default-features = false, features = [
     "union",
 ] }
 ruint = { version = "1.15.0", default-features = false, features = ["alloc"] }
+cfg-if = "1.0"
 
 # serde
 serde = { version = "1.0", default-features = false, optional = true, features = [
diff --git a/src/nibbles.rs b/src/nibbles.rs
index 3785dfe..8c8cbf7 100644
--- a/src/nibbles.rs
+++ b/src/nibbles.rs
@@ -1,8 +1,9 @@
+use cfg_if::cfg_if;
 use core::{
     cmp::{self, Ordering},
     fmt,
     mem::MaybeUninit,
-    ops::{Bound, RangeBounds},
+    ops::{Bound, Deref, RangeBounds},
     slice,
 };
 use ruint::aliases::U256;
@@ -131,8 +132,8 @@ impl Ord for Nibbles {
 
         // Slice to the loop iteration range to enable bound check
         // elimination in the compiler
-        let lhs = &self.nibbles.as_le_slice()[U256::BYTES - l..];
-        let rhs = &other.nibbles.as_le_slice()[U256::BYTES - l..];
+        let lhs = &as_le_slice(&self.nibbles)[U256::BYTES - l..];
+        let rhs = &as_le_slice(&other.nibbles)[U256::BYTES - l..];
 
         for i in (0..l).rev() {
             match lhs[i].cmp(&rhs[i]) {
@@ -335,12 +336,19 @@ impl Nibbles {
         let length = data.len() * 2;
         debug_assert!(length <= NIBBLES);
 
-        let mut nibbles = U256::ZERO;
+        cfg_if! {
+            if #[cfg(target_endian = "little")] {
+                let mut nibbles = U256::ZERO;
+                let nibbles_slice = nibbles.as_le_slice_mut();
+            } else {
+                let mut nibbles_slice = [0u8; 32];
+            }
+        }
 
         // Source pointer is at the beginning
         let mut src = data.as_ptr().cast::<u8>();
         // Move destination pointer to the end of the little endian slice
-        let mut dst = nibbles.as_le_slice_mut().as_mut_ptr().add(U256::BYTES);
+        let mut dst = nibbles_slice.as_mut_ptr().add(U256::BYTES);
         // On each iteration, decrement the destination pointer by one, set the destination
         // byte, and increment the source pointer by one
         for _ in 0..data.len() {
@@ -349,6 +357,12 @@ impl Nibbles {
             src = src.add(1);
         }
 
+        cfg_if! {
+            if #[cfg(target_endian = "big")] {
+                let nibbles = U256::from_le_bytes(nibbles_slice);
+            }
+        }
+
         Self { length, nibbles }
     }
 
@@ -494,7 +508,7 @@ impl Nibbles {
     pub fn get_byte_unchecked(&self, i: usize) -> u8 {
         self.assert_index(i);
         if i % 2 == 0 {
-            self.nibbles.as_le_slice()[U256::BYTES - i / 2 - 1]
+            as_le_slice(&self.nibbles)[U256::BYTES - i / 2 - 1]
         } else {
             self.get_unchecked(i) << 4 | self.get_unchecked(i + 1)
         }
@@ -551,9 +565,9 @@ impl Nibbles {
 
         // Fast path for even-even and odd-odd sequences
         if self.len() % 2 == other.len() % 2 {
-            return self.nibbles.as_le_slice()
+            return as_le_slice(&self.nibbles)
                 [(NIBBLES - self.len()) / 2..(NIBBLES - self.len() + other.len()) / 2]
-                == other.nibbles.as_le_slice()[(NIBBLES - other.len()) / 2..];
+                == as_le_slice(&other.nibbles)[(NIBBLES - other.len()) / 2..];
         }
 
         let mut i = 0;
@@ -586,7 +600,7 @@ impl Nibbles {
     #[track_caller]
     pub fn get_unchecked(&self, i: usize) -> u8 {
         self.assert_index(i);
-        let byte = self.nibbles.as_le_slice()[U256::BYTES - i / 2 - 1];
+        let byte = as_le_slice(&self.nibbles)[U256::BYTES - i / 2 - 1];
         if i % 2 == 0 {
             byte >> 4
         } else {
@@ -615,13 +629,31 @@ impl Nibbles {
     #[inline]
     pub unsafe fn set_at_unchecked(&mut self, i: usize, value: u8) {
         let byte_index = U256::BYTES - i / 2 - 1;
+
         // SAFETY: index checked above
-        let byte = unsafe { &mut self.nibbles.as_le_slice_mut()[byte_index] };
+        cfg_if! {
+            if #[cfg(target_endian = "little")] {
+                let byte = unsafe { &mut self.nibbles.as_le_slice_mut()[byte_index] };
+            } else {
+                // Big-endian targets must first copy the nibbles to a little-endian slice.
+                // Underneath the hood, `as_le_slice` will perform a stack copy, and we
+                // replace the underlying `nibbles` after we've updated the given nibble.
+                let mut le_copy = as_le_slice(&self.nibbles);
+                let byte = &mut le_copy.to_mut()[byte_index];
+            }
+        }
+
         if i % 2 == 0 {
             *byte = *byte & 0x0f | value << 4;
         } else {
             *byte = *byte & 0xf0 | value;
         }
+
+        // For big-endian targets, replace the underlying U256 with the mutated LE slice.
+        #[cfg(target_endian = "big")]
+        {
+            self.nibbles = U256::from_le_slice(&le_copy);
+        }
     }
 
     /// Returns the first nibble of this nibble sequence.
@@ -945,7 +977,7 @@ unsafe fn pack_to_unchecked(nibbles: &Nibbles, out: &mut [MaybeUninit<u8>]) {
     let byte_len = nibbles.len().div_ceil(2);
     debug_assert!(out.len() >= byte_len);
     // Move source pointer to the end of the little endian slice
-    let mut src = nibbles.nibbles.as_le_slice().as_ptr().add(U256::BYTES);
+    let mut src = as_le_slice(&nibbles.nibbles).as_ptr().add(U256::BYTES);
     // Destination pointer is at the beginning of the output slice
     let mut dst = out.as_mut_ptr().cast::<u8>();
     // On each iteration, decrement the source pointer by one, set the destination byte, and
@@ -1012,6 +1044,59 @@ fn panic_invalid_index(len: usize, i: usize) -> ! {
     panic!("index out of bounds: {i} for nibbles of length {len}");
 }
 
+/// Internal container for owned/borrowed byte slices.
+enum ByteContainer<'a, const N: usize> {
+    /// Borrowed variant holds a reference to a slice of bytes.
+    #[cfg_attr(target_endian = "big", allow(unused))]
+    Borrowed(&'a [u8]),
+    /// Owned variant holds a fixed-size array of bytes.
+    #[cfg_attr(target_endian = "little", allow(unused))]
+    Owned([u8; N]),
+}
+
+impl<'a, const N: usize> ByteContainer<'a, N> {
+    /// Returns a mutable reference to the underlying byte array, converting from borrowed to owned
+    /// if necessary.
+    ///
+    /// ## Panics
+    /// Panics if the current variant is `Borrowed` and the slice length is less than `N`.
+    #[cfg_attr(target_endian = "little", allow(unused))]
+    pub(crate) fn to_mut(&mut self) -> &mut [u8; N] {
+        match self {
+            ByteContainer::Borrowed(slice) => {
+                let mut array = [0u8; N];
+                array[..N].copy_from_slice(&slice[..N]);
+                *self = ByteContainer::Owned(array);
+                self.to_mut()
+            }
+            ByteContainer::Owned(ref mut array) => array,
+        }
+    }
+}
+
+impl<'a, const N: usize> Deref for ByteContainer<'a, N> {
+    type Target = [u8];
+
+    fn deref(&self) -> &Self::Target {
+        match self {
+            ByteContainer::Borrowed(slice) => slice,
+            ByteContainer::Owned(array) => array.as_slice(),
+        }
+    }
+}
+
+/// Returns a little-endian byte slice representation of the given [`U256`] value.
+#[inline]
+const fn as_le_slice(x: &U256) -> ByteContainer<'_, { U256::BYTES }> {
+    cfg_if! {
+        if #[cfg(target_endian = "little")] {
+            ByteContainer::Borrowed(x.as_le_slice())
+        } else {
+            ByteContainer::Owned(x.to_le_bytes())
+        }
+    }
+}
+
 #[cfg(test)]
 mod tests {
     use super::*;