Background: Malaria remains a major public health challenge in sub-Saharan Africa, where asymptomatic infections continue to hinder elimination efforts. Although the clinical and epidemiological consequences of microscopic infections are well documented, the health implications of submicroscopic Plasmodium falciparum infections remain poorly understood, particularly in Ghana. This study assessed the burden of submicroscopic P. falciparum infections and their association with antimalarial drug resistance markers among outpatients attending Korle Bu Teaching Hospital. Methods: A cross-sectional study involving 345 participants was conducted. Malaria infection was assessed using mRDT, blood smear microscopy, and LAMP-PCR for parasite detection and species identification. Antimalarial drug resistance markers were analyzed by multiplex PCR and Oxford Nanopore sequencing. Statistical analysis was performed using STATA version 14, applying Pearson’s chi-square test and logistic regression. Results: The overall prevalence of asymptomatic P. falciparum infection was 35.0% (117/334), with 18.9% microscopic and 16.1% submicroscopic infections. The wild-type pfcrt K76 allele, associated with chloroquine susceptibility, was highly prevalent (90.1%). Conclusions: Asymptomatic P. falciparum infections are common in this population, with a substantial proportion occurring at submicroscopic levels. The high prevalence of chloroquine-susceptible parasites and identified transmission hotspots underscore the need for sensitive diagnostics and targeted interventions to support malaria elimination efforts in Ghana.