diff --git a/packages/vite/src/node/optimizer/index.ts b/packages/vite/src/node/optimizer/index.ts
index d9b5d4897d667e..f50b0730096c96 100644
--- a/packages/vite/src/node/optimizer/index.ts
+++ b/packages/vite/src/node/optimizer/index.ts
@@ -61,6 +61,7 @@ export interface DepsOptimizer {
   delayDepsOptimizerUntil: (id: string, done: () => Promise<any>) => void
   registerWorkersSource: (id: string) => void
   resetRegisteredIds: () => void
+  ensureFirstRun: () => void
 
   options: DepOptimizationOptions
 }
diff --git a/packages/vite/src/node/optimizer/optimizer.ts b/packages/vite/src/node/optimizer/optimizer.ts
index 9a331e9db90ab4..37a3aef745b4f3 100644
--- a/packages/vite/src/node/optimizer/optimizer.ts
+++ b/packages/vite/src/node/optimizer/optimizer.ts
@@ -83,6 +83,7 @@ export async function initDepsOptimizer(
     registerWorkersSource,
     delayDepsOptimizerUntil,
     resetRegisteredIds,
+    ensureFirstRun,
     options: config.optimizeDeps
   }
 
@@ -521,12 +522,28 @@ export async function initDepsOptimizer(
   let seenIds = new Set<string>()
   let workersSources = new Set<string>()
   let waitingOn: string | undefined
+  let firstRunEnsured = false
 
   function resetRegisteredIds() {
     registeredIds = []
     seenIds = new Set<string>()
     workersSources = new Set<string>()
     waitingOn = undefined
+    firstRunEnsured = false
+  }
+
+  // If all the inputs are dependencies, we aren't going to get any
+  // delayDepsOptimizerUntil(id) calls. We need to guard against this
+  // by forcing a rerun if no deps have been registered
+  function ensureFirstRun() {
+    if (!firstRunEnsured && !firstRunCalled && registeredIds.length === 0) {
+      setTimeout(() => {
+        if (!firstRunCalled && registeredIds.length === 0) {
+          getDepsOptimizer(config)?.run()
+        }
+      }, runOptimizerIfIdleAfterMs)
+    }
+    firstRunEnsured = true
   }
 
   function registerWorkersSource(id: string): void {
@@ -559,7 +576,7 @@ export async function initDepsOptimizer(
         waitingOn = next.id
         const afterLoad = () => {
           waitingOn = undefined
-          if (!workersSources.has(next.id)) {
+          if (!firstRunCalled && !workersSources.has(next.id)) {
             if (registeredIds.length > 0) {
               runOptimizerWhenIdle()
             } else {
diff --git a/packages/vite/src/node/plugins/optimizedDeps.ts b/packages/vite/src/node/plugins/optimizedDeps.ts
index 3eff36bd1bc13e..3db6d850f7f286 100644
--- a/packages/vite/src/node/plugins/optimizedDeps.ts
+++ b/packages/vite/src/node/plugins/optimizedDeps.ts
@@ -108,8 +108,12 @@ export function optimizedDepsBuildPlugin(config: ResolvedConfig): Plugin {
       if (!metadata || !depsOptimizer?.isOptimizedDepFile(id)) {
         return
       }
+
+      depsOptimizer?.ensureFirstRun()
+
       const file = cleanUrl(id)
       // Search in both the currently optimized and newly discovered deps
+      // If all the inputs are dependencies, we aren't going to get any
       const info = optimizedDepInfoFromFile(metadata, file)
       if (info) {
         try {