The current study used the network meta-analysis to investigate the effects of early reading interventions with different combinations of phonological processing, decoding, fluency, vocabulary, and reading comprehension among students with reading difficulties (RD) in or before Grade 3. We aimed to test two reading intervention hypotheses: The ingredient-interaction model (various skill combinations produce various effects) and the active-ingredient model (there is the most effective skill or skill combination). Based on 100 studies and over 24,000 participants, results showed across word reading, fluency, and reading comprehension outcomes, 1) multi-skill interventions were more effective than single-skill interventions, 2) the word-focused combination (phonics, fluency, and vocabulary) and the comprehensive combination (addressing all skills) were consistently effective, and 3) intervention effects generally held across different situations (moderators). These findings have two key implications for the intervention and theory of RD in young students. First, interventions should move beyond single-skill instruction to a multi-skill approach that simultaneously teaches foundational skills like phonics, fluency, and vocabulary, alongside reading comprehension. Second, unlike strategy-oriented interventions, where a large number of components can lead to cognitive overload, multiple-component knowledge-based reading interventions create synergistic effects.