Introduction Serous effusion cytopathology is a minimally invasive, cost-effective procedure and plays a crucial role in diagnosing a spectrum of pathological conditions, ranging from benign to malignant. The International System for Reporting Serous Fluid Cytopathology (ISRSFC) offers a standardized framework for reporting serous effusions, aiding in better communication and clinical decision-making. Aims and objectives This study aimed to categorize effusions using the ISRSFC reporting system. In addition, we sought to estimate the risk of malignancy (ROM) for each diagnostic category and evaluate the diagnostic performance of conventional smear versus cell block techniques. Materials and methods This cross-sectional study was conducted in the Department of Pathology over one year. We applied the ISRSFC criteria to serous effusions and categorized them accordingly. The ROM for each category was assessed with histopathology serving as the gold standard. Then, the diagnostic performance including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy was evaluated using conventional smear and cell block techniques. Results The study included 185 serous effusion cases, with ages ranging from two months to 85 years. The male-to-female ratio was 1.1:1. Most effusions were pleural fluids constituting about 133 cases (71.9%), followed by peritoneal fluids (47 cases, 25.4%) and pericardial fluids (five cases, 2.7%). Among the fluids, four (2.2%) were diagnosed as non-diagnostic (ND), 152 (82.2%) as negative for malignancy (NFM), four (2.2%) as atypia of undetermined significance (AUS), nine (4.8%) as suspicious for malignancy (SFM), and 16 (8.6%) as malignant (MAL). The overall ROM was 25% for ND, 8.5% for NFM, 50% for AUS, 77% for SFM, and 100% for MAL. The sensitivity, negative predictive value (NPV), and diagnostic accuracy were superior when combining conventional smear with the cell block technique. Conclusions Our findings underscore the use of ISRSFC in categorizing effusion samples, assessing the ROM, and guiding clinical management. Moreover, our study highlights the benefits of employing a combined approach using conventional smears and cell blocks for enhanced diagnostic accuracy in serous effusions.