This study aimed to develop and evaluate an integrated methodological guide for enhancing students’ research skills in the Physical Methods of Chemical Research course. A Research and Development (R&D) approach combined with a quasi-experimental design was employed, comprising four stages: development, expert validation, practicality evaluation, and effectiveness testing. The methodological guide integrated Inquiry-Based Learning (IBL), Problem-Based Learning (PBL), laboratory activities, Bloom’s Taxonomy-based multilevel tasks, and STEM-oriented activities within a unified research-oriented learning framework. The study involved 112 third-year university students, and the effectiveness of the guide was assessed using a pretest-posttest design across six research skill indicators: interpretation, analysis, inference, evaluation, explanation, and self-regulation. The results confirmed the validity and practical applicability of the developed guide. The student practicality assessment reached 91.7%, while observed student activities reached 89.16%. The teacher practicality assessment was 77.9%, and observed teacher activities reached 90.12%. Effectiveness analysis showed that the experimental group achieved a high N-gain (M = 0.7558, SD = 0.13940), compared with the moderate N-gain of the control group (M = 0.3887, SD = 0.20794). The effect size was large (Cohen’s d = 2.07379), indicating a substantial effect of the intervention on students’ research skills. Improvements were observed across all six indicators, although evaluation demonstrated a comparatively lower gain and required further instructional support. In addition, 79.78% of student responses were classified in the good category. These findings demonstrate that the integrated methodological guide is a valid, practical, and effective instructional resource for systematically integrating theoretical knowledge, laboratory investigation, inquiry, problem solving, data analysis, scientific reasoning, and reflection to enhance students’ research skills in university chemistry education.