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Lymphedema, hydrocele, and acute adenolymphangitis (ADL) are chronically disabling consequences in patients with lymphatic filariasis (LF). Provision of morbidity management and disability prevention and concurrent mass drug administration of anthelmintics are two pillars for elimination of LF. This study assessed the impact of strict hygiene protocols with or without doxycycline on the progression of filarial lymphedema. A randomized, placebo-controlled, double-blind trial was conducted in two regions in Tanzania. We enrolled 362 participants with lymphedema stages 1-3 assigned into three treatment groups of doxycycline 200 mg once daily, doxycycline 100 mg once daily, or matching placebo for 42 days in addition to hygiene measures. The participants were followed every 2 months for 2 years. Twenty-four months after treatment onset, 17.7% of participants displayed improved limb conditions, including 15/104 (14.4%) in the doxycycline 200 mg group, 16/105 (15.2%) in the doxycycline 100 mg group, and 25/107 (23.4%) in the placebo group. During the first 6 months after treatment, the number of participants experiencing an ADL attack was significantly lower in the doxycycline groups than in the placebo group. The study also found that hygiene was one of the factors associated with preventing the occurrence of acute attacks over the whole study period. Doxycycline 100 mg was a significant factor for the halt of progression (odds ratio: 0.53, P = 0.0239) when both legs if affected at baseline were considered. These findings emphasize the importance of practicing hygiene in reducing the occurrence of ADL attacks and the benefits of doxycycline with regards to acute attacks and halt of progression.