Aim: The purpose of the study was to compare the efficacy of oral fluconazole (150 mg single dose) and vaginal clotrimazole (1 gm daily during 7 days) in the treatment of vulvovaginal candidiasis (VVC) in patients with High Vaginal Swab (HVS) positive infections with regard to clinical curing and mycological elimination. Methodology: A randomized controlled trial was done at the Department of Obstetrics and Gynecology at Capital Development Authority (CDA) Hospital, Islamabad, in a period of six months. The patients were selected by non-probability consecutive sampling (114 in each group). The women were randomly divided into oral fluconazole group (Group A) and vaginal clotrimazole group (Group B). Treatment efficacy was determined by lack of fungal cultures and absence of vulvovaginal symptoms on day 7. The Statistical Package for Social Sciences (SPSS) 24 version was used to analyze the data and Chi-square tests were conducted to compare the efficacy across groups. Results: The findings show that oral fluconazole (150 mg single dose) was superior to vaginal clotrimazole (1 gm daily 7 days) in the treatment of the VVC. Fluconazole group recorded an efficacy rate of 90% as compared to 70% in clotrimazole. Subgroup analysis revealed that fluconazole was especially effective in patients with a shorter symptom duration, with an efficacy rate of 92% versus 75% with clotrimazole. Even in patients with a longer duration of the symptoms, fluconazole continued to perform better (88% vs. 65% with clotrimazole). The efficacy of fluconazole was 90% in younger patients (18-25 years) as opposed to clotrimazole (68%). In patients with BMI <25 (kg/m²), the efficacy of oral fluconazole was 90%, while vaginal clotrimazole showed 75% efficacy. For patients with BMI ≥25 (kg/m²), oral fluconazole had an efficacy of 88%, while vaginal clotrimazole was less effective at 60%. Conclusion: Oral fluconazole was more effective in the treatment of VVC, which provided prompt resolution of the symptoms in comparison with vaginal clotrimazole. Nonetheless, vaginal clotrimazole can also be considered as a viable alternative in case of recurrence and complicated cases of VVC since it acts locally and is less likely to be absorbed into the bloodstream.